The representative volatile flavor compounds with their aroma flavor characteristics found in cooked meat. [References: 13, 14, 20, 15, 27]
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"6952",leadTitle:null,fullTitle:"Irrigation in Agroecosystems",title:"Irrigation in Agroecosystems",subtitle:null,reviewType:"peer-reviewed",abstract:"The agroecosystem is one of the most fascinating, purposely human-created functional units, by which human species made a huge leap from predators and nomads to food growers (agriculturists). Irrigation is one of the oldest and still one of the most effective agricultural practices for providing continuous and quality foodstuffs.",isbn:"978-1-78984-924-0",printIsbn:"978-1-78984-923-3",pdfIsbn:"978-1-83881-743-5",doi:"10.5772/intechopen.73607",price:119,priceEur:129,priceUsd:155,slug:"irrigation-in-agroecosystems",numberOfPages:184,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"1afe3f365612ea9b4f35942c69792f63",bookSignature:"Gabrijel Ondrašek",publishedDate:"January 23rd 2019",coverURL:"https://cdn.intechopen.com/books/images_new/6952.jpg",numberOfDownloads:11402,numberOfWosCitations:22,numberOfCrossrefCitations:22,numberOfCrossrefCitationsByBook:2,numberOfDimensionsCitations:48,numberOfDimensionsCitationsByBook:2,hasAltmetrics:1,numberOfTotalCitations:92,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 18th 2018",dateEndSecondStepPublish:"February 8th 2018",dateEndThirdStepPublish:"April 9th 2018",dateEndFourthStepPublish:"June 28th 2018",dateEndFifthStepPublish:"August 27th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"46939",title:"Prof.",name:"Gabrijel",middleName:null,surname:"Ondrasek",slug:"gabrijel-ondrasek",fullName:"Gabrijel Ondrasek",profilePictureURL:"https://mts.intechopen.com/storage/users/46939/images/system/46939.jpg",biography:"Gabrijel Ondrasek, PhD, is employed at the University of Zagreb, Faculty of Agriculture, Croatia, as a full professor at the Department of Soil Amelioration. His academic and scientific opus is orientated towards sustainable management of natural resources (water, soils) in the agro-environment, notably exposed to disturbed water balance on the soil–plant route, excessive salinity, metal contamination, and their environmental implications.",institutionString:"University of Zagreb",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"University of Zagreb",institutionURL:null,country:{name:"Croatia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"307",title:"Agroecology",slug:"agroecology"}],chapters:[{id:"63637",title:"Introductory Chapter: Irrigation after Millennia - Still One of the Most Effective Strategies for Sustainable Management of Water Footprint in Agricultural Crops",doi:"10.5772/intechopen.81189",slug:"introductory-chapter-irrigation-after-millennia-still-one-of-the-most-effective-strategies-for-susta",totalDownloads:916,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:null,signatures:"Gabrijel Ondrasek",downloadPdfUrl:"/chapter/pdf-download/63637",previewPdfUrl:"/chapter/pdf-preview/63637",authors:[{id:"46939",title:"Prof.",name:"Gabrijel",surname:"Ondrasek",slug:"gabrijel-ondrasek",fullName:"Gabrijel Ondrasek"}],corrections:null},{id:"62253",title:"Informational Entropy Approach for Rating Curve Assessment in Rough and Smooth Irrigation Ditch",doi:"10.5772/intechopen.78975",slug:"informational-entropy-approach-for-rating-curve-assessment-in-rough-and-smooth-irrigation-ditch",totalDownloads:887,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The assessment of water discharge in open channel flow is one of the most crucial issues for hydraulic engineers in the fields of water resources management, river dynamics, eco-hydraulics, irrigation, hydraulic structure design, etc. Recent studies state that the entropy velocity law allows expeditive methodology for discharge estimation and rating curve development due to the simple mathematical formulation and implementation. A lot of works have been developed based on the entropy velocity profile supporting measurements in lab for rating curve assessment in regular ditch flows showing a good performance. The present work deals with the use of entropy velocity profile approach in order to give a general framework of threats and opportunities related to robust operational application of such laws in the field of rating curve assessment. The analysis has been carried on a laboratory flume with regular roughness under controlled boundary conditions and different stages generating an exhaustive dashboard for the better appraisal of the approaches. Finally, entropy model may represent a robust and useful tool for the water discharge assessment in rough ditches.",signatures:"Greco Michele",downloadPdfUrl:"/chapter/pdf-download/62253",previewPdfUrl:"/chapter/pdf-preview/62253",authors:[{id:"242048",title:"Prof.",name:"Michele",surname:"Greco",slug:"michele-greco",fullName:"Michele Greco"}],corrections:null},{id:"62528",title:"Irrigation Management Practices and Their Influence on Fruit Agroecosystem",doi:"10.5772/intechopen.79569",slug:"irrigation-management-practices-and-their-influence-on-fruit-agroecosystem",totalDownloads:1140,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Annual crops are highly sensitive to water stress, so efficient water management in orchards enhance the production and sustainability of fruit cultivation. The performance of fruit tree in terms of fruit yield, fruit size and quality and long term productivity is highly dependent on irrigation and different species respond to it differently, It is known fact that the amount of fresh water available for agriculture use is decreasing and there is a need to use water efficiently either by using water saving irrigation techniques or by scheduling irrigation as per the plant’s need. The scheduling of irrigation in fruit crops has gained significant importance for last one decade due to viewed rise in temperature, changing pattern of rainfall and reduction of fresh water for irrigation purposes especially for farmers indulged in fruit culture. The recent research phenology and physiology of the fruit trees in orchard management with major emphasis on water management practices e.g. deficit irrigation can influence an optimal nutrient equilibrium in soil, improve irrigation efficiency and prevent soil erosions. On this basis, work on irrigation scheduling based on evapotranspiration demand was studied in fruit agroecosystem to maintain high yield and quality of fruit crop.",signatures:"Gaganpreet Kour and Parshant Bakshi",downloadPdfUrl:"/chapter/pdf-download/62528",previewPdfUrl:"/chapter/pdf-preview/62528",authors:[{id:"242620",title:"Dr.",name:"Gaganpreet",surname:"Kour",slug:"gaganpreet-kour",fullName:"Gaganpreet Kour"}],corrections:null},{id:"61435",title:"Using Smartphone Technologies to Manage Irrigation",doi:"10.5772/intechopen.77304",slug:"using-smartphone-technologies-to-manage-irrigation",totalDownloads:1054,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Numerous tools have been developed with the aim of improving irrigation scheduling. Some methods involve using soil moisture sensors and irrigating based on soil moisture thresholds. Others may be based on evapotranspiration models. More novel techniques include irrigating based on the water status within the target crop. However, growers have been reluctant to adopt many of these irrigation scheduling methods because they may be too cumbersome to use, require specialized equipment, or are perceived as too risky compared to traditional methods. Recently, smartphone applications have been developed that schedule irrigation based on crop coefficients and real-time weather data. Called the SmartIrrigation™ application (smartirrigationapps.org), these tools have the potential to aid farmers in conserving water and nutrients, while maintaining crop yields. These applications were developed by the University of Florida and include such crops as citrus (Citrus spp.), cotton (Gossypium hirsutum), turfgrass, blueberries (Vaccinium darrowii), and several vegetables. These applications can be downloaded for free by the public and utilize real-time data from nearby weather stations in Georgia and Florida. To determine the efficacy of the new SmartIrrigation™ applications for watermelons and tomatoes, trials were conducted over 2 years in southern Georgia, USA.",signatures:"Timothy Coolong, Luke Miller and George Vellidis",downloadPdfUrl:"/chapter/pdf-download/61435",previewPdfUrl:"/chapter/pdf-preview/61435",authors:[{id:"243498",title:"Associate Prof.",name:"Timothy",surname:"Coolong",slug:"timothy-coolong",fullName:"Timothy Coolong"},{id:"243500",title:"BSc.",name:"Luke",surname:"Miller",slug:"luke-miller",fullName:"Luke Miller"},{id:"243501",title:"Prof.",name:"George",surname:"Vellidis",slug:"george-vellidis",fullName:"George Vellidis"}],corrections:null},{id:"64340",title:"Deficit Irrigation in Mediterranean Fruit Trees and Grapevines: Water Stress Indicators and Crop Responses",doi:"10.5772/intechopen.80365",slug:"deficit-irrigation-in-mediterranean-fruit-trees-and-grapevines-water-stress-indicators-and-crop-resp",totalDownloads:1431,totalCrossrefCites:10,totalDimensionsCites:14,hasAltmetrics:1,abstract:"In regions with Mediterranean climate, water is the major environmental resource that limits growth and production of plants, experiencing a long period of water scarcity during summer. Despite the fact that most plants developed morphological, anatomical, physiological, and biochemical mechanisms that allow to cope with such environments, these harsh summer conditions reduce growth, yield, and fruit quality. Irrigation is implemented to overcome such effects. Conditions of mild water deficit imposed by deficit irrigation strategies, with minimal effects on yield, are particularly suitable for such regions. Efficient irrigation strategies and scheduling techniques require the quantification of crop water requirements but also the identification of pertinent water stress indicators and their threshold. This chapter reviews the scientific information about deficit irrigation recommendations and thresholds concerning water stress indicators on peach trees, olive trees, and grapevines, as case studies.",signatures:"Anabela Fernandes-Silva, Manuel Oliveira, Teresa A. Paço and Isabel\nFerreira",downloadPdfUrl:"/chapter/pdf-download/64340",previewPdfUrl:"/chapter/pdf-preview/64340",authors:[{id:"81075",title:"Prof.",name:"Anabela",surname:"Fernandes-Silva",slug:"anabela-fernandes-silva",fullName:"Anabela Fernandes-Silva"},{id:"181227",title:"Dr.",name:"Manuel",surname:"Oliveira",slug:"manuel-oliveira",fullName:"Manuel Oliveira"},{id:"245447",title:"Prof.",name:"Teresa",surname:"Paço",slug:"teresa-paco",fullName:"Teresa Paço"},{id:"245449",title:"Prof.",name:"Isabel",surname:"Ferreira",slug:"isabel-ferreira",fullName:"Isabel Ferreira"}],corrections:null},{id:"62796",title:"Water Footprint Differences of Producing Cultivars of Selected Crops in New Zealand",doi:"10.5772/intechopen.77509",slug:"water-footprint-differences-of-producing-cultivars-of-selected-crops-in-new-zealand",totalDownloads:869,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Water footprint (WF) is a measure of the amount of water used to produce goods and services. It is a very important concept on indicating how much water can be consumed to complete a process of growing or processing a product at a particular location. However, paucity of water footprint information in countries facing increased competition for water resources between industries limits market access and profit optimization. Water footprint differences of producing selected cultivars of potato, oca and pumpkin squash were determined under irrigation and rain-fed regimes. All crop husbandry practices were followed in potato, oca (3.3 plants m−2) and pumpkin squash (2.2 plants m−2). Water footprint was determined as the ratio of volume of evapotranspiration for irrigated and rain-fed crops plus grey water to total yield. The consumptive water use for the rain-fed crop was 75, 65 and 69% of the irrigated oca, potato and pumpkin squash, respectively, with high water consumption in heritage cultivars. The water footprint was low in pumpkin squash and highest in oca, while potato cultivars were intermediate. Irrigation reduced water footprint especially in crops more responsive to irrigation. Farmers should focus on improving the harvest index and irrigation to reduce water footprint.",signatures:"Isaac R. Fandika, Peter D. Kemp, James P. Millner and Davie Horne",downloadPdfUrl:"/chapter/pdf-download/62796",previewPdfUrl:"/chapter/pdf-preview/62796",authors:[{id:"241780",title:"Dr.",name:"Isaac",surname:"Fandika",slug:"isaac-fandika",fullName:"Isaac Fandika"}],corrections:null},{id:"61593",title:"Water Quality in Irrigated Paddy Systems",doi:"10.5772/intechopen.77339",slug:"water-quality-in-irrigated-paddy-systems",totalDownloads:1126,totalCrossrefCites:0,totalDimensionsCites:9,hasAltmetrics:1,abstract:"Irrigated paddy rice (Oryza sativa L.) is a staple food for roughly half of the world’s population. Concerns over water quality have arisen in recent decades, particularly in China, which is the largest rice-producing country in the world and has the most intensive use of nutrients and water in rice production. On the one hand, the poor water quality has constrained the use of water for irrigation to paddy systems in many areas of the world. On the other hand, nutrient losses from paddy production systems contribute to contamination and eutrophication of freshwater bodies. Here, we review rice production, water requirement, water quality issues, and management options to minimize nutrient losses from paddy systems. We conclude that management of nutrient source, rate, timing, and placement should be combined with the management of irrigation and drainage water to reduce nitrogen and phosphorus losses from paddies. More research is needed to identify cost-effective monitoring approaches and mitigation options, and relevant extension and policy should be enforced to achieve water quality goals. The review is preliminarily based on China’s scenario, but it would also provide valuable information for other rice-producing countries.",signatures:"Jian Liu, Hongbin Liu, Ruliang Liu, MG Mostofa Amin, Limei Zhai,\nHaiming Lu, Hongyuan Wang, Xubo Zhang, Yitao Zhang, Ying Zhao\nand Xiaodong Ding",downloadPdfUrl:"/chapter/pdf-download/61593",previewPdfUrl:"/chapter/pdf-preview/61593",authors:[{id:"58990",title:"Dr.",name:"Ying",surname:"Zhao",slug:"ying-zhao",fullName:"Ying Zhao"},{id:"243104",title:"Dr.",name:"Jian",surname:"Liu",slug:"jian-liu",fullName:"Jian Liu"},{id:"253811",title:"Prof.",name:"Hongbin",surname:"Liu",slug:"hongbin-liu",fullName:"Hongbin Liu"},{id:"253812",title:"Dr.",name:"Ruliang",surname:"Liu",slug:"ruliang-liu",fullName:"Ruliang Liu"},{id:"253813",title:"Dr.",name:"M G Mostofa",surname:"Amin",slug:"m-g-mostofa-amin",fullName:"M G Mostofa Amin"},{id:"253871",title:"Dr.",name:"Limei",surname:"Zhai",slug:"limei-zhai",fullName:"Limei Zhai"},{id:"253872",title:"Dr.",name:"Hongyuan",surname:"Wang",slug:"hongyuan-wang",fullName:"Hongyuan Wang"},{id:"253873",title:"Dr.",name:"Xubo",surname:"Zhang",slug:"xubo-zhang",fullName:"Xubo Zhang"},{id:"253874",title:"Dr.",name:"Yitao",surname:"Zhang",slug:"yitao-zhang",fullName:"Yitao Zhang"},{id:"253875",title:"Dr.",name:"Xiaodong",surname:"Ding",slug:"xiaodong-ding",fullName:"Xiaodong Ding"}],corrections:null},{id:"61837",title:"Management of Plant Disease Epidemics with Irrigation Practices",doi:"10.5772/intechopen.78253",slug:"management-of-plant-disease-epidemics-with-irrigation-practices",totalDownloads:1722,totalCrossrefCites:5,totalDimensionsCites:13,hasAltmetrics:0,abstract:"Adequate water provision to roots is essential to warrant sustainable harvests of agricultural crops globally. However, water applied in excess or in deficit may result in the development of many fungal and bacterial plant diseases, which compromise produce yield and quality. Leaf wetness duration, soil water tension and related water variables impact several aspects of different plant disease cycles, such as the sporulation, survival of pathogen propagules, their dispersal to new hosts, germination and infection. Irrigation is thus arguably the most important cultural practice in the management of plant diseases, especially in the context of the quest of a more sustainable, less chemically dependent agriculture. The technology of water application and method of irrigation have been profusely studied as to their direct relation to plant diseases. Irrigation management has a strong impact on the disease severity and epidemic progress rates of many plant pathosystems, ranging from leaf blights to vascular wilts. In addition, plant virus vector population levels and vector dispersal are also affected by the method of irrigation. This chapter reviews experimental data on the effect of different irrigation configurations and management systems on some representative plant diseases.",signatures:"Adalberto C. Café-Filho, Carlos Alberto Lopes and Maurício Rossato",downloadPdfUrl:"/chapter/pdf-download/61837",previewPdfUrl:"/chapter/pdf-preview/61837",authors:[{id:"107911",title:"Prof.",name:"Adalberto",surname:"Café-Filho",slug:"adalberto-cafe-filho",fullName:"Adalberto Café-Filho"},{id:"243127",title:"Dr.",name:"Mauricio",surname:"Rossato",slug:"mauricio-rossato",fullName:"Mauricio Rossato"},{id:"243128",title:"Dr.",name:"Carlos Alberto",surname:"Lopes",slug:"carlos-alberto-lopes",fullName:"Carlos Alberto Lopes"}],corrections:null},{id:"63233",title:"Paddy Fields as Artificial and Temporal Wetland",doi:"10.5772/intechopen.80581",slug:"paddy-fields-as-artificial-and-temporal-wetland",totalDownloads:1368,totalCrossrefCites:3,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Paddy cultivation plays a significant and vital role on rice production. Most of the global population depends on the 480 million tons of rice produced each year as the basis for their lives. While about 90% of the world’s 160 million hectares of paddy fields are in Asian countries, mainly in monsoon regions, paddies are also seen in North America and Africa, even in dry regions. Most of the paddy fields are flooded naturally or artificially during rice production period. In the case that paddy fields are kept submerged artificially, hydraulic structures are required. Irrigated paddy fields produce traditionally much rice, taking befits of stable water supply and continuous ponding. Paddy fields are simultaneously performing other functions for local environment, including climate mitigation, flood control, groundwater recharge, biodiversity, and ecosystem development. On the other hand, since paddy fields require much water and modify the original and natural hydrological regime, they might cause adverse effect on local environment. Much water supply by irrigation sometimes requires drainage system, which also might alter local water balance. In this chapter, implication of paddy fields as artificial and temporal wetland is reviewed comprehensively with various aspects, focusing mainly on their role for local hydrological environment.",signatures:"Tsugihiro Watanabe",downloadPdfUrl:"/chapter/pdf-download/63233",previewPdfUrl:"/chapter/pdf-preview/63233",authors:[{id:"243864",title:"Prof.",name:"Tsugihiro",surname:"Watanabe",slug:"tsugihiro-watanabe",fullName:"Tsugihiro Watanabe"}],corrections:null},{id:"62632",title:"Traditional Water Meadows: A Sustainable Management Type for the Future?",doi:"10.5772/intechopen.79429",slug:"traditional-water-meadows-a-sustainable-management-type-for-the-future-",totalDownloads:889,totalCrossrefCites:0,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Traditional meadow irrigation techniques were once widespread throughout Europe and served as a method of grassland intensification before the era of mineral fertilization. Close to Landau (Palatinate), Germany, there are several hectares of traditionally irrigated water meadows that are irrigated twice a year in parts since the medieval age or irrigation has been reinitiated since the 1990. In a research project “WasserWiesenWerte”, we analyzed the ecological and socio-economic value of meadow irrigation. We compared extensively to semi-intensively used meadows with fertilizer application between 0 and 80 kg N/ha per year which were either irrigated or nonirrigated. The results were very motivating. Biomass production is increased by about one-third with irrigation. At the same time, several species groups did not decrease in frequency and diversity in the meadows under irrigation. In contrast, some especially rare species seemed to even profit. Ditch structures turned out to be especially important refuges for sensible meadow species and added a large quantity of additional species to the landscape diversity. We propose that the revitalization of traditional irrigation techniques should be considered when extensively managed grassland—especially hay meadows—are prone to either intensification or abandonment.",signatures:"Constanze Buhk, Jens Schirmel, Gerlach Rebekka and Oliver Frör",downloadPdfUrl:"/chapter/pdf-download/62632",previewPdfUrl:"/chapter/pdf-preview/62632",authors:[{id:"244825",title:"Ph.D.",name:"Constanze",surname:"Buhk",slug:"constanze-buhk",fullName:"Constanze Buhk"},{id:"256052",title:"Dr.",name:"Jens",surname:"Schirmel",slug:"jens-schirmel",fullName:"Jens Schirmel"},{id:"256053",title:"MSc.",name:"Rebekka",surname:"Gerlach",slug:"rebekka-gerlach",fullName:"Rebekka Gerlach"},{id:"256054",title:"Prof.",name:"Oliver",surname:"Frör",slug:"oliver-fror",fullName:"Oliver Frör"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"8489",title:"Drought",subtitle:"Detection and Solutions",isOpenForSubmission:!1,hash:"d7c48c817f290b0ed1e97a940a68a52b",slug:"drought-detection-and-solutions",bookSignature:"Gabrijel Ondrasek",coverURL:"https://cdn.intechopen.com/books/images_new/8489.jpg",editedByType:"Edited by",editors:[{id:"46939",title:"Prof.",name:"Gabrijel",surname:"Ondrasek",slug:"gabrijel-ondrasek",fullName:"Gabrijel Ondrasek"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4566",title:"Agroecology",subtitle:null,isOpenForSubmission:!1,hash:"9e35a4ff7bee4ab82eab2c6b3f441789",slug:"agroecology",bookSignature:"Vytautas Pilipavičius",coverURL:"https://cdn.intechopen.com/books/images_new/4566.jpg",editedByType:"Edited by",editors:[{id:"169359",title:"Dr.",name:"Vytautas",surname:"Pilipavicius",slug:"vytautas-pilipavicius",fullName:"Vytautas Pilipavicius"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6301",title:"Vegetation",subtitle:null,isOpenForSubmission:!1,hash:"5c1b7f22f2f926f8d59ea56f2fe84c6f",slug:"vegetation",bookSignature:"Allan Sebata",coverURL:"https://cdn.intechopen.com/books/images_new/6301.jpg",editedByType:"Edited by",editors:[{id:"143409",title:"Dr.",name:"Allan",surname:"Sebata",slug:"allan-sebata",fullName:"Allan Sebata"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6485",title:"Sustainability of Agroecosystems",subtitle:null,isOpenForSubmission:!1,hash:"4ed7b8c6bce44bfaddb83c0365793742",slug:"sustainability-of-agroecosystems",bookSignature:"Alexandre Bosco de Oliveira",coverURL:"https://cdn.intechopen.com/books/images_new/6485.jpg",editedByType:"Edited by",editors:[{id:"77880",title:"Dr.",name:"Alexandre",surname:"De Oliveira",slug:"alexandre-de-oliveira",fullName:"Alexandre De Oliveira"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9345",title:"Sustainable Crop Production",subtitle:null,isOpenForSubmission:!1,hash:"5135c48a58f18229b288f2c690257bcb",slug:"sustainable-crop-production",bookSignature:"Mirza Hasanuzzaman, Marcelo Carvalho Minhoto Teixeira Filho, Masayuki Fujita and Thiago Assis Rodrigues Nogueira",coverURL:"https://cdn.intechopen.com/books/images_new/9345.jpg",editedByType:"Edited by",editors:[{id:"76477",title:"Prof.",name:"Mirza",surname:"Hasanuzzaman",slug:"mirza-hasanuzzaman",fullName:"Mirza Hasanuzzaman"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6560",title:"Plant Competition in Cropping Systems",subtitle:null,isOpenForSubmission:!1,hash:"664e0a97f4494932f6c0461f9a6e7bd6",slug:"plant-competition-in-cropping-systems",bookSignature:"Daniel Dunea",coverURL:"https://cdn.intechopen.com/books/images_new/6560.jpg",editedByType:"Edited by",editors:[{id:"180202",title:"Associate Prof.",name:"Daniel",surname:"Dunea",slug:"daniel-dunea",fullName:"Daniel Dunea"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10499",title:"Next-Generation Greenhouses for Food Security",subtitle:null,isOpenForSubmission:!1,hash:"456f82c97eafad5734cd36c48e167781",slug:"next-generation-greenhouses-for-food-security",bookSignature:"Redmond R. 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From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"861",title:"Nanomaterials",subtitle:null,isOpenForSubmission:!1,hash:"f32b97a9aa541939cb212373d471d477",slug:"nanomaterials",bookSignature:"Mohammed Muzibur Rahman",coverURL:"https://cdn.intechopen.com/books/images_new/861.jpg",editedByType:"Edited by",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5403",title:"Advances in Colloid Science",subtitle:null,isOpenForSubmission:!1,hash:"38413a6aefb978b024eac803fba6c354",slug:"advances-in-colloid-science",bookSignature:"Mohammed Muzibur Rahman and Abdullah Mohamed Asiri",coverURL:"https://cdn.intechopen.com/books/images_new/5403.jpg",editedByType:"Edited by",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7230",title:"Recent Advances in Ionic Liquids",subtitle:null,isOpenForSubmission:!1,hash:"cebbba5d7b2b6c41fafebde32f87f90b",slug:"recent-advances-in-ionic-liquids",bookSignature:"Mohammed Muzibur Rahman",coverURL:"https://cdn.intechopen.com/books/images_new/7230.jpg",editedByType:"Edited by",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5308",title:"Nanofiber Research",subtitle:"Reaching New Heights",isOpenForSubmission:!1,hash:"e5d2ad58b1840ec81e587914d52f5e0b",slug:"nanofiber-research-reaching-new-heights",bookSignature:"Mohammed Muzibur Rahman and Abdullah M. Asiri",coverURL:"https://cdn.intechopen.com/books/images_new/5308.jpg",editedByType:"Edited by",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6218",title:"Carbon Nanotubes",subtitle:"Recent Progress",isOpenForSubmission:!1,hash:"9f38af20209e9d816b7d57ecbba386b9",slug:"carbon-nanotubes-recent-progress",bookSignature:"Mohammed Muzibur Rahman and Abdullah Mohamed Asiri",coverURL:"https://cdn.intechopen.com/books/images_new/6218.jpg",editedByType:"Edited by",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5777",title:"Electrochemical Sensors Technology",subtitle:null,isOpenForSubmission:!1,hash:"c290f7095446d3908041a5185fded2e5",slug:"electrochemical-sensors-technology",bookSignature:"Mohammed Muzibur Rahman and Abdullah Mohamed Asiri",coverURL:"https://cdn.intechopen.com/books/images_new/5777.jpg",editedByType:"Edited by",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7671",title:"Concepts of Semiconductor Photocatalysis",subtitle:null,isOpenForSubmission:!1,hash:"549e8caa1b260cea0dd3fe688cd126f5",slug:"concepts-of-semiconductor-photocatalysis",bookSignature:"Mohammed Rahman, Anish Khan, Abdullah Asiri and Inamuddin Inamuddin",coverURL:"https://cdn.intechopen.com/books/images_new/7671.jpg",editedByType:"Edited by",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6856",title:"Gold Nanoparticles",subtitle:"Reaching New Heights",isOpenForSubmission:!1,hash:"23e172496e46e18712a901308d074cfb",slug:"gold-nanoparticles-reaching-new-heights",bookSignature:"Mohammed Rahman and Abdullah Mohammed Asiri",coverURL:"https://cdn.intechopen.com/books/images_new/6856.jpg",editedByType:"Edited by",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5848",title:"Recent Progress in Organometallic Chemistry",subtitle:null,isOpenForSubmission:!1,hash:"aa9478b98a858b7c57bf056ac5c6e197",slug:"recent-progress-in-organometallic-chemistry",bookSignature:"Mohammed Muzibur Rahman and Abdullah Mohamed Asiri",coverURL:"https://cdn.intechopen.com/books/images_new/5848.jpg",editedByType:"Edited by",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9206",title:"Importance of Selenium in the Environment and Human Health",subtitle:null,isOpenForSubmission:!1,hash:"e21bd2a386a2d078fe53a4d1658e44bf",slug:"importance-of-selenium-in-the-environment-and-human-health",bookSignature:"Mohammed Muzibur Rahman, Abdullah Mohamed Asiri, Anish Khan and Inamuddin",coverURL:"https://cdn.intechopen.com/books/images_new/9206.jpg",editedByType:"Edited by",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"37707",title:"Principle of Meat Aroma Flavors and Future Prospect",doi:"10.5772/51110",slug:"principle-of-meat-aroma-flavors-and-future-prospect",body:'\n\t\tThe population growth fact of the world has been much quickly increasing through the years. As reported by the United Nations Population Fund (UNFPA) the estimated world population of 6.1 billion in the year 2000 and reached to 7 billion in the year 2011, increased 0.9 billion people only after 10 years. The population increases always proportionally accompany to the consumption demands in which including foods. Calculating the global meat consumption only and based on the data collected from IFPRI/ FAO/ILRI by Delgado et al (1999) [1] suggested that global production and consumption of meat will continue to raise from 233 million metric tons in the year 2000 to 300 million metric tons in 2020. On the other hand, income growth of people in most of the countries especially in the developed countries has been significantly increasing in the recent years. Combination of the large populations together with a high-income that will give a big pressure for the food producers in general and meat producers in particular. As a consequence, higher income growth in countries has led to an increase in living standards and changes in consumer diets to include a higher proportion of meat and meat products. While, productivity and provision of meats on the markets has been limited and rising costs of production resulting in not keeping pace with the strong growth in demand, that has caused a rise in meat prices.
\n\t\t\tAlthough, a strong demand for meat amounts but consumers are getting quite fastidious to choose meat and meat products since consumer’s preference for meat buying is strongly based on quality, freshness and hygiene. Quality factors are very important in the meat purchasing behavior of consumers including marbling (intramuscular fat tissues), texture, color, tenderness and especially flavor characteristics.
\n\t\t\tAroma flavor characteristics of cooked meat in particular play the most important level in eating quality of meat, acceptance and preference by consumers. The aroma flavor characteristics of cooked meats are derived from volatile flavor components which derive from thermally induced reactions occurring during heating via the four pathways including (1) Maillard reaction of amino acid or peptides with reducing sugars, (2) Lipid oxidation, (3) interaction between Maillard reaction products with lipid-oxidized products and (4) vitamin degradation during cooking [2]. Aroma flavor is perceived through the nostrils (orthonasal aroma) it gives the first impression of a certain food. When the food is placed in the mouth, the volatile flavor compounds will be transferred through the pharynx to the olfactory receptors (retronasal aroma). It has been reported that flavors together with other sensory attributes such as tenderness and juiciness are specially considered the most important criterion of acceptability and the palatability of meat that affects consumer’s purchasing decisions [3,4]. It has been well known that all volatile flavor components are organic and they have low molecular weight [5]. The chemical structures of volatile flavor classes are varied widely including aldehydes, ketones, hydrocarbons, pyrazines, acids, esters, alcohols, nitrogen and sulfur-containing compounds and other heterocyclic compounds as well. Due to the differences in chemical structures therefore their volatility is also quite different.
\n\t\t\tMany factors have been found to be as influences on the aroma flavors of cooked meat. Rabe et al (2003) [6] found that among all food constituents, lipids generally have the greatest influence on production of aroma flavor components, as they not only reduce the vapour pressure of most flavor compounds. Otherwise, Kinsella (1990) [7] showed that aroma compounds are more lipophilic than hydrophilic therefore fats act as a solvents for aroma compounds reducing their volatility. In addition to these effects, other factors such as diets, breed, sex, chiller ageing, meat pH, cooking conditions which all also affect the flavor [8, 9, 40, 11]
\n\t\t\tWith the crucial importance of aroma flavor of meat for the acceptance and preference of consumers and as well as the factors influencing the generation of aroma flavor compounds as mentioned above, the present chapter aims to highlight the basic information regarding aroma flavor components in terms of mechanisms of formation pathways; current techniques being used for detection; factors that affect aroma flavors; and final ideas and as well as suggestions are also given out to improve flavor quality attributes according to criterion of acceptability, satisfaction and the palatability for consumer.
\n\t\tFlavor characteristics of cooked meat are directly detected by the nose (i.e., olfactory receptors) before and during chewing. Raw meat has little aroma and only blood-like taste, meat develops its aroma flavor characteristics during cooking as the result of complex interaction of precursors derived from both the lean and fat compositions of meat generating volatile flavor compounds that contribute to meat flavor [12]. To date, approximately thousands of volatile flavor compounds have been detected and identified in cooked meat. There is a large number of these compounds contributing to the flavor characteristics of cooked meat have been identified in previous works [13, 14, 15, 16, 17, 18, 19].
\n\t\t\t\tAs mentioned above, regarding the chemical structures of volatile flavor classes, among that the heterocyclic compounds especially those containing sulfur are the important flavor compounds produced in the Maillard reaction providing savory, meaty, roasty and boiled flavor characteristics. While, lipid-degraded- compounds which give ‘fatty’ aromas to cooked meat and compounds which determine some of the aroma flavor differences between meats from different species [20]. The individual volatile compounds have been found to determine distinct aroma flavors of cooked meat represent; dimethylsulfide, 2-butanone, ethyl acetate, 2- and 3-methylbutanal, 2-heptanone, dimethyl trisulphide and nonanal were detected as key flavor compounds of cooked Irish Angus beef, while methional, 2,4-nonadienal and bezothiazole were characterized as meaty, oily notes in cooked Belgian Blue, Limousin and Aberdeen Angus beefs [21]. Kerscher & Grosch, (1997) [22] reported that 2-furfurylthiol, 4-hydroxy-2,5-dimethyl-3(2
\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t|
Methional | \n\t\t\t\t\t\t\tCooked potato, meaty | \n\t\t\t\t\t\t
E,2-nonenal | \n\t\t\t\t\t\t\tFatty | \n\t\t\t\t\t\t
E,E,2,4-decadienal | \n\t\t\t\t\t\t\tFatty | \n\t\t\t\t\t\t
Benzenacetaldehyde | \n\t\t\t\t\t\t\tSweet, honey | \n\t\t\t\t\t\t
E,E,2,4-nonedienal | \n\t\t\t\t\t\t\tFatty | \n\t\t\t\t\t\t
Decanal | \n\t\t\t\t\t\t\tSweet, fruity, like aldehydes, roasty | \n\t\t\t\t\t\t
Heptanal | \n\t\t\t\t\t\t\tFruity, fatty, sweet, oil | \n\t\t\t\t\t\t
Nonanal | \n\t\t\t\t\t\t\tSweet, fatty, green | \n\t\t\t\t\t\t
Undecanal | \n\t\t\t\t\t\t\tSweet, pungent, green | \n\t\t\t\t\t\t
E,2-heptenal | \n\t\t\t\t\t\t\tFatty | \n\t\t\t\t\t\t
E,2-heptenal | \n\t\t\t\t\t\t\tFatty | \n\t\t\t\t\t\t
Hexanal | \n\t\t\t\t\t\t\tGreen, fatty | \n\t\t\t\t\t\t
E,2-hexenal | \n\t\t\t\t\t\t\tGreen | \n\t\t\t\t\t\t
E,Z,2,6-nonadienal | \n\t\t\t\t\t\t\tCucumber | \n\t\t\t\t\t\t
Undecanal | \n\t\t\t\t\t\t\tSweet, pungent, green | \n\t\t\t\t\t\t
2-methylbutanal | \n\t\t\t\t\t\t\tPungent, sweet, roasty | \n\t\t\t\t\t\t
E,2-undecenal | \n\t\t\t\t\t\t\tSweet, fruity, fatty | \n\t\t\t\t\t\t
2,E-dodecenal | \n\t\t\t\t\t\t\tSweet, fruity, roasty, pungent | \n\t\t\t\t\t\t
Ethanol | \n\t\t\t\t\t\t\tGrilled (weak), acetaldehyde-like | \n\t\t\t\t\t\t
3-methylbutanal | \n\t\t\t\t\t\t\tMeaty, fish, rotten, aldehyde,valeric acid, fatty | \n\t\t\t\t\t\t
Octanal | \n\t\t\t\t\t\t\tGreen, lemon, citrus, aldehyde | \n\t\t\t\t\t\t
E,E,2,4-heptadienal | \n\t\t\t\t\t\t\tAldehyde, green, broth, spicy | \n\t\t\t\t\t\t
Propanal | \n\t\t\t\t\t\t\tcaramel, sweet, alcoholic, “cooked”, broth, spicy | \n\t\t\t\t\t\t
Butanal | \n\t\t\t\t\t\t\tsmoky, fish, amylic, aldehyde-enal or dienal | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t|
2-octanone | \n\t\t\t\t\t\t\tFruity, musty | \n\t\t\t\t\t\t
2-decanone | \n\t\t\t\t\t\t\tFruity, musty | \n\t\t\t\t\t\t
2-dodecanone | \n\t\t\t\t\t\t\tFruity, musty | \n\t\t\t\t\t\t
1-octen-3-one | \n\t\t\t\t\t\t\tfresh, mushrooms, pungent, rubbery | \n\t\t\t\t\t\t
3-octanone | \n\t\t\t\t\t\t\tFruity, nutty, moldy, fatty, earthy | \n\t\t\t\t\t\t
2,5-dimethyl-4-hydroxy-3(2H)-furanone | \n\t\t\t\t\t\t\tRoasted almonds, sweet | \n\t\t\t\t\t\t
4,5-dihydro-5-propyl-2(3H)-furanone | \n\t\t\t\t\t\t\tFruity, fatty, sweet, pungent, roasty | \n\t\t\t\t\t\t
2,3-butanedione | \n\t\t\t\t\t\t\tSweet, buttery | \n\t\t\t\t\t\t
2-heptanone | \n\t\t\t\t\t\t\tCitrus grapefruit, limonene, floral, cheese | \n\t\t\t\t\t\t
2,3-pentanedione | \n\t\t\t\t\t\t\tbuttery, lemon-like, sweet, fruity | \n\t\t\t\t\t\t
2-nonanone | \n\t\t\t\t\t\t\tHot milk, soap, green, fruity, floral | \n\t\t\t\t\t\t
3-octen-2-one | \n\t\t\t\t\t\t\tNut, crushed bug, earthy, spicy, sweet, mushroom, | \n\t\t\t\t\t\t
6-Methyl 2-heptanone | \n\t\t\t\t\t\t\tCloves, menthol | \n\t\t\t\t\t\t
2-undecanone | \n\t\t\t\t\t\t\tFruity | \n\t\t\t\t\t\t
2,2,6-Trimethylcyclohexanone | \n\t\t\t\t\t\t\tMint, acetone | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t|
1-octen-3-ol | \n\t\t\t\t\t\t\tMushroom | \n\t\t\t\t\t\t
Cyclobutanol | \n\t\t\t\t\t\t\tRoasted | \n\t\t\t\t\t\t
1-heptanol | \n\t\t\t\t\t\t\tFragrant, woody, oily, green, fatty, winey, sap | \n\t\t\t\t\t\t
1-hexanol | \n\t\t\t\t\t\t\tWoody, cut grass, chemical-winey, fatty, fruity | \n\t\t\t\t\t\t
2-Ethyl 1-hexanol | \n\t\t\t\t\t\t\tResin, flower, green | \n\t\t\t\t\t\t
1-octanol | \n\t\t\t\t\t\t\tPenetrating aromatic odor, fatty, waxy, citrus, oily, | \n\t\t\t\t\t\t
2-Octen-1-ol | \n\t\t\t\t\t\t\tGreen citrus | \n\t\t\t\t\t\t
1-pentanol | \n\t\t\t\t\t\t\tMild odor, fuel oil, fruit, balsamic | \n\t\t\t\t\t\t
Propanol | \n\t\t\t\t\t\t\tAlcoholic | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t|
Ethenylbenzene | \n\t\t\t\t\t\t\tPungent, aromatic, fragrant, roasty | \n\t\t\t\t\t\t
1-undecen | \n\t\t\t\t\t\t\tFatty, burnt, nutty, rubbery | \n\t\t\t\t\t\t
Hexane | \n\t\t\t\t\t\t\tFaint peculiar odor | \n\t\t\t\t\t\t
(Z)-3-Octene | \n\t\t\t\t\t\t\tFruity, old apples | \n\t\t\t\t\t\t
Pentane | \n\t\t\t\t\t\t\tVery slight warmed-over flavor, oxidized | \n\t\t\t\t\t\t
Styrene | \n\t\t\t\t\t\t\tPenetrating odor, sweet smell | \n\t\t\t\t\t\t
Tridecane | \n\t\t\t\t\t\t\tAlkane | \n\t\t\t\t\t\t
Tetradecane | \n\t\t\t\t\t\t\tAlkane | \n\t\t\t\t\t\t
Ethenylbenzene | \n\t\t\t\t\t\t\tAromatic, fragrant, roasty | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t|
2-ethyl-3,5-dimethylpyrazin | \n\t\t\t\t\t\t\tBurnt, fragrant, meaty, green | \n\t\t\t\t\t\t
2-ethenyl-3,6(5)-dimethylpyrazine | \n\t\t\t\t\t\t\tSweet, cooked rice, fatty | \n\t\t\t\t\t\t
2-ethyl-3,6-dimethylpyrazine | \n\t\t\t\t\t\t\tBurnt, roasty | \n\t\t\t\t\t\t
2,3-diethyl-5-methylpyrazine | \n\t\t\t\t\t\t\tmeaty, roasty, fragrant, sweet | \n\t\t\t\t\t\t
2,5-dimethylpyrazine | \n\t\t\t\t\t\t\tFried rice, popcorn, pungent, green | \n\t\t\t\t\t\t
2-ethenyl-5(6)-methylpyrazine | \n\t\t\t\t\t\t\tRoasty break-like, cooked rice, coffee-like | \n\t\t\t\t\t\t
2,5-dimethylpyrazine | \n\t\t\t\t\t\t\tFried rice, popcorn, pungent, green | \n\t\t\t\t\t\t
2-ethyl-5-methylpyrazine | \n\t\t\t\t\t\t\tFruity, sweet, pungent | \n\t\t\t\t\t\t
2-ethenyl-5(6)-methylpyrazine | \n\t\t\t\t\t\t\tSmoky, roasty, break-like, cooked rice, popcorn | \n\t\t\t\t\t\t
2-ethyl-3,6-dimethylpyrazine | \n\t\t\t\t\t\t\tBurnt, pungent, roasty | \n\t\t\t\t\t\t
2-ethenyl-3,6(5)-dimethylpyrazine | \n\t\t\t\t\t\t\tPungent, sweet, cooked rice, fatty | \n\t\t\t\t\t\t
2,3-diethyl-5-methylpyrazine | \n\t\t\t\t\t\t\tMeaty, roasty, fragrant, sweet | \n\t\t\t\t\t\t
2-isopentyl-3,6-dimethylpyrazine | \n\t\t\t\t\t\t\tSweet, fragrant, fatty, fruity, pungent | \n\t\t\t\t\t\t
Sulfur & nitrogen containing compounds | \n\t\t\t\t\t\t|
2-fufurylthiol | \n\t\t\t\t\t\t\tRoasty | \n\t\t\t\t\t\t
2-acetyl-1-pyrroline | \n\t\t\t\t\t\t\tRoasted, sweet | \n\t\t\t\t\t\t
2-formyl-5-methylthiophene | \n\t\t\t\t\t\t\tSulfurous | \n\t\t\t\t\t\t
2-methyl-3-furanthiol | \n\t\t\t\t\t\t\tMeaty, sweet, sulfurous | \n\t\t\t\t\t\t
Benzylthiol | \n\t\t\t\t\t\t\tSulphurous | \n\t\t\t\t\t\t
2,4-dimethylthiazole | \n\t\t\t\t\t\t\tRubber y, moldy, fruity, pungent | \n\t\t\t\t\t\t
2-acetylthiazole | \n\t\t\t\t\t\t\tRoasted | \n\t\t\t\t\t\t
Dimethyltrisulfide | \n\t\t\t\t\t\t\tFragrant, musty, roasty, rubbery | \n\t\t\t\t\t\t
2-acethylthiophene | \n\t\t\t\t\t\t\tSulphurous, sweet | \n\t\t\t\t\t\t
Bis(2-methyl-3-furyl)disulfide | \n\t\t\t\t\t\t\tMeaty-like | \n\t\t\t\t\t\t
Benzothiazole | \n\t\t\t\t\t\t\tMetallic | \n\t\t\t\t\t\t
Dimethyldisulfide | \n\t\t\t\t\t\t\tMoldy, pungent, rubbery, onion-like | \n\t\t\t\t\t\t
2,4-dimethylthiazole | \n\t\t\t\t\t\t\tRubbery, moldy, fruity, pungent | \n\t\t\t\t\t\t
4,5-dimethylthiazole | \n\t\t\t\t\t\t\tSmoky, roasty, fragrant, nutty | \n\t\t\t\t\t\t
2-methylchinoxaline | \n\t\t\t\t\t\t\tAromatic, roasted, nutty, sweet, fruity, fatty | \n\t\t\t\t\t\t
3-mercapto-2-butanone | \n\t\t\t\t\t\t\tFried onion, sulfury, cooked meat | \n\t\t\t\t\t\t
2-mercapto-3-pentanone | \n\t\t\t\t\t\t\tBrothy, mashed potatoes meaty, roast meat | \n\t\t\t\t\t\t
2-[(methyldithio)methyl]furan | \n\t\t\t\t\t\t\tBrothy, spices, roast, fatty | \n\t\t\t\t\t\t
3-[(2-furanylmethyl)dithio]-2-butanone | \n\t\t\t\t\t\t\tonion, burnt rubber, burnt wood | \n\t\t\t\t\t\t
Earlier studies on meat flavor, researchers recognized that the low molecular weight, water-soluble compounds and fats in meat constituents are the most important precursor of aroma flavor characteristics of cooked meat [28, 29]. The flavor precursor of meat namely, free sugars, free amino acids, peptides, vitamin, sugar phosphate, nucleotide-bound sugars and nucleotides [30, 31, 32, 33], all of them are able to either participate the Maillard reaction or oxidation/degradation and interaction on heating to generate volatile flavor compounds then create the final aroma flavor characteristics of cooked meat. It is suggested that these precursor components found to contribute to the development of meaty flavor, while the adipose tissues and intramuscular fat not only occupy an important role in development of flavor characteristics of cooked meat but also contribute to the characteristic-specific species flavors. This means that the distinct flavor characteristics between the meats from different species are due to the intramuscular fat content and not from water-soluble precursor compounds. The details on flavor precursors of meat found in the past years are showed in Table 2. However, researchers found that the roles of these flavor precursors in the development of flavor characteristics of cooked meat are not similar. Macey et al (1964) [28] found some sugars present in beef such as glucose, fructose, mannose and ribose, in that ribose was the most heat-labile sugar among these whereas fructose was the most stable. Among the amino acids present in meat, systein and systine are two sulfur-containing amino acids, the reaction of these with other sugars lead to formation of many sulfur-containing flavor compounds [34], while the reaction of other non-sulfur containing amino acids with sugars dominated by the nitrogen-containing products such as pyrazines [72]. In the recent years, researchers have found that the flavor precursor components in meats are influenced by several factors. Koutsidis et al (2008) [31] indicated that diets significantly affected the reducing sugars in beef
\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
Free amino acids \n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\tSystine; systeine; glycine; lysine; alanine; valine; isoleucine; leucine; threonine; serine; proline; asparagines; aspartic acid; methionine; glutamic acid; phenylalanine; glutamine; ornithine; histidine; tyrosine; tryptophan; arginine. | \n\t\t\t\t\t\t\t[38,39,40, 31,3232] | \n\t\t\t\t\t\t
Reducing sugars | \n\t\t\t\t\t\t\tRibose; glucose; xylose; starch; mannose; fructose; maltose; mannose 6-phosphate, glucose 6-phosphate; fructose 6-phosphate; ribose 6-phosphate. | \n\t\t\t\t\t\t\t[38,39,72, 41,31,32] | \n\t\t\t\t\t\t
Fats/ lipids | \n\t\t\t\t\t\t\tTriglycerides and phospholipids Oleic acid (C18:1n-9) Linoleic acid (C18:2n-6) Linolenic acid (C18:3n-3) and etc. | \n\t\t\t\t\t\t\t[42,19, 43,34] | \n\t\t\t\t\t\t
Vitamin | \n\t\t\t\t\t\t\tThiamin | \n\t\t\t\t\t\t\t[33,44] | \n\t\t\t\t\t\t
Nucleotides and peptides | \n\t\t\t\t\t\t\tGlutathione; carnosine inosine; inosine monophosphate; inosine 5’-monophosphate; guanosine 5-monophosphate; creatine; creatinine; Hypoxanthine and etc. | \n\t\t\t\t\t\t\t[45,44, 31,32] | \n\t\t\t\t\t\t
The representative precursors of meat flavor.
Maillard reaction, a non-enzymatic browning which plays an important role in generation of volatile flavor compounds and appearances of the cooked foods, it is due to most of important volatile flavor compounds found in cooked foods are originated from this reaction. Otherwise, Maillard reaction also can produce antioxidative components and toxicological implications as well. However, in the present chapter we are focusing on the Maillard reaction in relation to aroma flavor characteristics, particularly the formation of volatile flavor compounds in cooked meat. Maillard reaction was firstly mentioned in the early time, 1912 by Maillard [46] since he wanted to investigate the browning reaction between glucose and glycine. After that many studies focused on determining the fundaments and mechanisms of this reaction [47, 48, 49].
\n\t\t\t\t\tGeneral stages of Maillard reaction showing the formations of flavor compounds (based on van Boekel, 2006) [
The Maillard reaction is taken placed with the participation of reducing sugars (e.g., ribose, glucose) and free amino compounds (e.g., amino acids, amines, peptides, proteins, ammonia) at certain heating condition to produce the Maillard products, and usually this reaction is divided into three main stages. In which the firstly initial stage starts with a condensation between a reducing sugar and an amino group, the loss of water from this molecule produces an amine that is able to cyclise resulting in formation of an N-glycosylamine (a sugar attached to NR2 group) or called Amadori product. The next intermediate stage involves the rearrangement and decomposition of the Amadori product to release amino group and sugar fragmentation. The final stage of Maillard reaction is leading to dehydration, fragmentation, polymeration and cyclization reactions. A general scheme of the Maillard reaction is given in Figure 1.
\n\t\t\t\t\t\tStrecker degradation mechanisms, a part of Maillard reaction
The formation of H2S from the Strecker degradation of cysteine
Among events occurring in the Maillard reaction, Strecker degradation is one of the quite important events, in which amino acids are undergone degradation processes (oxidative deamination and decarboxylation) in the presence of a dicarbonyls compound formed from Maillard reaction. The Strecker degradation processes lead to formation of aldehydes (e.g., fufural) and aminoketone (Figure 2). Especially the other important intermediate products such as H2S, NH3, etc are also formed from the Strecker degradation by sulphur-containing amino acids such as cystein and systine (Figure 3); all of these intermediate products can further react with other compounds or with each other to produce low and high molecular weight end flavor compounds.
\n\t\t\t\tKinetic scheme of flavor formation by Maillard reaction (Jousse et al., 2002) [
\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t
Pyrazines | \n\t\t\t\t\t\t\t\tCooked, roasted, toasted, baked cereals | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Alkylpyrazines | \n\t\t\t\t\t\t\t\tNutty, roasted | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Alkylpyridines | \n\t\t\t\t\t\t\t\tGreen, bitter, astringent, burnt | \n\t\t\t\t\t\t\t\tUnpleasant flavor | \n\t\t\t\t\t\t\t
Acetylpyridines | \n\t\t\t\t\t\t\t\tCaracker-like | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Pyrroles | \n\t\t\t\t\t\t\t\tCereal –like | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Furan, furanones, pyranone | \n\t\t\t\t\t\t\t\tSweet, burnt, pungent, caramel-like | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Oxazoles | \n\t\t\t\t\t\t\t\tGreen, nutty, sweet | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Thiophenes | \n\t\t\t\t\t\t\t\tMeaty | \n\t\t\t\t\t\t\t\tFormed from heated meat by the reaction of systein and ribose | \n\t\t\t\t\t\t\t
Some representative classes of flavor compounds formed from the Maillard reaction (based on van Boekel, 2006) [51].
The formation of volatile flavor compounds in the Maillard reaction largely depend on the reactants (e.g., the nature of reducing sugars and amino acids participated) and also the catalytic condition (e.g., heating temperature, moisture, pH). For the type of reducing sugars and amino acids which determine the kinds of flavor compounds generated for instance, many sulfur-containing flavor compounds are formed from the Maillard reaction between systeine and ribose [34] whereas, the nitrogen-containing compounds (e.g., pyrazines) dominated in the Maillard reaction containing glucose and lysine [72]. Therefore, it should be noted that nature of reactants will require the kinds of Maillard products. For the catalytic condition of Maillard reaction, it usually influences the kinetics of flavor compound generation by Maillard reaction in that depending on each catalytic condition (temperature, pH and etc) will determine the yields and also kinds of Maillard products. The kinetic of flavor compound formation resembles the scheme in Figure 4 with 11 determining steps [50]. Based on the kinetic scheme it shows that there are many chemical classes of flavors are formed via the Maillard reaction, some of the representative classes associated with odor notes are showed in Table 3.
\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\tLipids and fatty acids play an important role in direct and indirect generating the volatile flavor compounds and some of them contributing to the aroma flavor characteristics of cooked meat. Therefore, the levels of fat contents and as well as fatty acids of meats should be concerned, and it has been reported that the fatty acids of meat are influenced by several factors but almost are the pre-harvest factors such as diets, feed regimes and breeds [52, 53, 54]. Based on our surveillance it seems that the fatty acid profiles significantly vary across the breeds even these breeds are fed with the same diets [55, 56, 57]. Both adipose tissue and intramuscular fat contents are constituted by fatty acids including saturated and unsaturated fatty acids which all are capable to get oxidized and degraded under a certain condition to create a prolific number of volatile flavor compounds [2]. Hundreds of volatile flavor compounds derived from lipid degradation have been found in cooked meat including aliphatic hydrocarbons, aldehydes, ketones, alcohols, carboxylic acids and esters. In general, the odor detection threshold values for the lipid-derived compounds are much higher than those for the sulfur and nitrogen-containing heterocyclic compounds which are formed from the water-soluble precursors via the Maillard reaction. Therefore, the aroma significance of many of these lipid-derived compounds is not as great as that for relatively low concentrations of the heterocyclic compounds. However, certain classes of compounds such as particular aldehydes included saturated and unsaturated aldehydes which containing from 6 to 10 carbons in the structures are major volatile components of all cooked meats and, therefore, they probably play an important part in meat aroma [20]. The oxidation of subcutaneous fat, adipose tissues and intramuscular fat occur in raw meat and continues under the catalysis of many factors such as metals, oxygen, light, heating and etc.
\n\t\t\t\tAmong the oxidation-induced factors for instance, lights (e.g., ultraviolet) is thought to be thermodynamically capable of production of free radicals directly in lipids, the principles of light-absorbing groups of lipids are double bonds, peroxide bonds and carbonyls which subsequently under the other steps to generate volatiles. And other factors such as oxygen, lypoxygenase, metals and etc which all also affect the lipid oxidation however that is another concern, in the present work we only consider on the heat effect that similar to cooking condition to induce the oxidation and degradation of fatty acids in producing volatile flavor compounds of cooked meat. The degrees of heating temperatures have been reported to affect variously lipid oxidation, in that high heating temperatures (e.g., frying, roasting) can have highly sufficient energies to break the single bonds (e.g., C-C or C-H) in the acyl back bonds to generate a lot of lipid alkyl radicals that participate the radical chain formation of oxidation [58]. Lower heating temperatures have lower energies which can break O-O bonds in traces of ROOH. Mottram (1985) [59] also stated that meat is cooked under boiled and lightly roasted conditions, lipid oxidation products dominated the detected compounds, and many of among them such as aldehydes, alcohols, ketones and lactones which have sufficiently low odor threshold to be contributors of meat aroma flavors.
\n\t\t\t\tEarly work of Mottram et al (1982) [60] found that lipid has a considerable role in meat flavor, when the adipose tissue is added to lean meat does not affect the lipid-derived flavor compounds. A later study by Mottram and Edwards (1983) [42] found that the removal of intramuscular fats and phospholipids from beef caused marked differences in flavor compounds and sensory characteristics as well. So that the intramuscular fat contents (marbling fats) and membrane lipids are the main source of volatile flavor components and make species-specific flavors. However, it has been demonstrated that high levels of lipids especially polyunsaturated fatty acid contents (PUFA) cause undesirable aroma flavors due to their PUFA-derived products lower or inhibit the formation of some heterocyclic Maillard products [42]. This phenomenon has recently been elucidated by researchers when they used model systems. In the model systems containing systeine, ribose and lipid (e.g., lecithin or individual fatty acids) the concentrations of heterocyclic compounds and especially sulfur-containing compounds were lower several times compared with the model system without lipid content [43, 38, 61, 34]. However, the interaction between the lipid-derived products with Maillard products to form volatile flavor components has been much considered in the previous studies and thought as the important pathway for formation of flavor compounds.
\n\t\t\t\tThiamin is considered as a source of meat flavor generated on heating. Researchers found that the thermal degradation of thiamin produces some ended and intermediate flavor compounds [62,63]. It was assumed that thermal degradation of thiamin is a quite complex reaction including various degradation pathways to produce interesting flavor compounds in which most of them contain one or more sulfur and/or nitrogen atoms, and many of them are heterocyclic structures. The thermal degradation of thiamin under the basic condition to produce several flavor compounds is illustrated in Figure 5.
\n\t\t\t\t\tIt was reported that the primary products of thermally-degraded thiamin including 4-methyl-5-(2-hydroxyethyl)thiazole which subsequently responds for formation of thiazoles and other sulfur compounds such as 5-hydroxy-3-mercaptopentan-2-one which then gives some sulfur-containing compounds such as thiophenes and furans as well [62]. Heating temperature and pH conditions have been showed to affect the degradation products of thiamin. At pH 5.0 and 7.0 the 2-methyl-3furanthiol and bis (2-methyl3-furyl) disulfide (meaty aroma) and thiophenes were the dominant aroma volatile compounds. But the levels of these meaty compounds decrease when increasing pH to 9.0 [64]. Similarly, a recent study by Dreher et al (2003) [65] also showed that the most significant thiamin thermal degradation products in the model reaction of orange juice containing 0.024 mM thiamin are 2-methyl-3-furanthiol and bis(2-methyl-3-furyl) disulfide produce intense meaty aromas. Otherwise, some other aroma-active compounds also were found such as 4, 5-dimethylthiazole (skunky, earthy), 3-thiophenethiol (meaty, cooked), 2-methyl-4, 5-dihydro-3(2H)-thiophenone (sour-fruity, musty, green), 2-acethylthiophene (burnt), 2-formyl-5-methylthiophene (meaty), and 2-methyl-3-(methyldithio) furan (meaty).
\n\t\t\t\tThe thermal degradation of thiamin under basic condition
The interaction between oxidized lipids and amino acids or proteins is very complex, in term of a consequence of the contribution of both lipid hydroperoxide and its secondary-oxidized products. This interaction may imply both the formation of physical complexes between the oxidized lipids and the amino acids or protein and the formation of various types of covalent bonds. Protein polymerizarion produced by reaction with peroxy free radicals generated during lipid peroxidation is known to occur during nonenzymatic browning [66, 67, 68]. However, in term of flavor study, the interaction between lipid-oxidized products (secondary products) with amino acids or proteins is the most concerned. Lipid-oxidized products are generic terms used to describe a mixture of aldehydes, alcohols, ketones and other products obtained by the decomposition of lipid hydroperoxides. Although it is not widely recognized, this decomposition does not necessarily imply the breakage of the lipid chain, and the formation of covalent bonds in the reaction between long chain oxidized lipids and amino acids and proteins has been described [69, 70]. This is a consequence of the existence of fatty acids that produce a complex and diverse mixture of lipid oxidation products that are able to react with the different reactive protein residues.
\n\t\t\t\t\tIn the Maillard reaction, amino acids can undergo the Strecker degradation process that subsequently generates some reactive radicals such as ammonia, hydrosulfide and etc which also are able to further react with the secondary oxidized products of lipid to produce volatile flavor compounds such as thiols, thiophenes, thiazoles and etc as showed in Figure 6.
\n\t\t\t\t\tThe interaction between lipid and Maillard reaction have extensively been studied in a number of studies using model systems containing amino acids and sugars in the presence of lipid [43, 61, 39, 34]. In these studies, systeine and ribose were used for Maillard reaction and in the presence of phospholipids from various sources including egg-yolk and beef. The reaction mixtures produced a lot of aroma volatiles which dominated by sulfur-containing components especially heterocyclics such as thiols and thiophenes. These studies also observed that the presence of phospholipids made a great reduction in amounts of these compounds. Famer and Mottram (1990) [61] also noted that beef-originated triglyceride has much less influence on amounts of heterocyclics than the phospholipids from beef do. The study also found that the addition of beef triglyceride to the Maillard reaction did not influence the sulfurous and rubbery aroma but when beef phospholipids were added resulting in higher meaty aroma note whereas the sulfurous notes were less. However, the Maillard reaction systems containing phospholipids usually had lower level of some meaty compounds especially 2-methyl-3-furanthiol this is due to the lipid limits generation of these compounds and only maintain theme at an optimum level in the reaction mixture.
\n\t\t\t\t\tThe interaction between lipid-oxidized products with Maillard products.
In general, in Maillard reaction mixtures containing lipids produce a lot of lipids-derived volatile compounds such as aldehydes, furans, hydrocarbons, alcohols and ketones. Furthermore, the reaction mixtures also containing the Maillard products such as H2S, NH3, etc. Which all are able to interact with each other to form new heterocyclic aroma volatile compounds as the consequences of the interactions between lipids with Maillard products. The most abundant compounds have been detected as results of the interactions are thiophene class such as 2-pentylthiophene, 2-hexylthiophene and thiol class such as 2-thiophenethiol, 2-furylmethanethiol, 2-methyl-3-furanthiol and etc [38, 61]. A recent study by Elmore and colleagues (2002) [34] concluded that breakdown products of polyunsaturated fatty acids especially are
Diet is as an important indicator to show the growth rate, performance, reproducibility effects and as well as meat quality of cattle. There has been an existed hypothesis of meat flavor changes due to feeding diets in which some works stated a large difference in meat flavor characteristics of the same cattle breed but fed on different diets. Early work by Melton (1983) [71] stated that steers fed with corn-based diets had more intense beef flavor (desirable flavor) than the same age steers fed based pasture or Bermuda pellets. A later study of Melton (1990) [10] found that the less desirable flavor of meat from cattle is mainly caused by several grass species. Conversely, no significant difference in flavors existed between the grass and grain diets-fed animals [73]. The less desirable flavors were also seen on meats from the hay diets-fed animals compared to corn silage diets [74], while Oltjen et al (1971) [75] showed the opposite results. It has been hypothesized that majority of flavor effects due to feeding of forages is mainly due to changes in fatty acid compositions. Fishy off-flavor was significantly higher in meat from grass-finished cattle with increasing unsaturated fatty acids [76]. Recently, researchers have attempted to higher level of PUFA in meat aiming to increase the health benefits by using the fat supplemented-diets (e.g., linseed, sunflower oil and fish oil) to cattle [77, 78], although these works have achieved an increase in several benefit fatty acids however, the detrimental effects on meat flavor characteristics appeared due to higher levels of PUFA [79]. A large number of studies regarding the effect of diets on volatile flavor compounds of cooked meat have been performed. Melton (1983) [71] also noted that the greatest difference in the flavors of meat from cattle fed on grass and grain-based diets is due to fatty acid concentration and type as fatty acids are the primary source of carbonyl. Suzuki and Bailey (1985) [80] indicated that higher concentrations of pentanoic,heptanoic, octanoic, nonanoic, decanoic, and dodecanoic acids were formed in the meat fat from grass-fed animals while heptanal, 2,3-octanedione, 3-hydroxyoctan-2-one, 2-decenal, 2-tridecanone, hexadecane, heptadecane, octodecane, d-dodecalactone, phyt-1-ene, neophytadiene, phyt-2-ene, an isomer of neophytadiene, 2-heptadecanone, dihydrophytol, and phytol with the terpenoids in much higher concentration due to rumen-fermented chlorophyll. Individual volatile flavor compounds like 4-heptanal, 2, 4-heptadienal and 2, 6-nonadienal (derived from C18:3n-3) and hexanal, 2-heptanal and 2, 4-decadienal (derived from C18:2n-6) found to be higher concentration in meats from grass and grain-fed animals, respectively [81]. Elmore et al (1997) [82] also reported that cooked meat from the animals that had been fed fish oil had considerably higher concentrations of saturated and unsaturated aldehydes than meat from the control. While, Descalzo et al (2005) [83] found that some classes of volatile flavor components affected by diets in which aldehydes increased in meat from concentrate diets-fed animals. In general, we can see that diets have a large influence on meat flavors due to directly affect the meat contents especially the intramuscular fat contents which play an important role in interaction and generation of volatile flavor compounds. On the other hand, it is worth noting that the uses of fat –supplemented diets to feed cattle may result in increases of important polyunsaturated fatty acids (e.g., n-3 fatty acids, DHA, EPA) which known to positively affect on consumers health however, a negative effect on meat flavors may appear due to these fatty acids not only produce some unexpected volatile compounds but also inhibit production of other Maillard products.
\n\t\t\tResearchers have reported that breed also affects volatile flavor components and then influence overall flavor notes of cooked meat. Elmore et al (2000) [25] stated that fifty-four compounds were affected by breed, 75% of which was Maillard reaction products. Over 40 compounds were present at higher levels in the Soay breed than in the Suffolk breed. Other sulfur-containing compounds present at higher levels in the Suffolks than the Soays were bis-(2-furylmethyl) disulfide and 2-methyl-4,5-dihydro-thiophene and the differences in sulfur and nitrogen-containing compounds could contribute to flavor differences between the two breeds. A study on pork flavors as affected by breeds also have found that twenty-three among the detected flavor compounds were significantly affected by breed. Based on sensory analysis indicated that cooked
For the sex effect, it has been reported that meat from bulls has a strong livery and blood flavors while meat from heifers has a strong characteristic flavor. The differences could be associated with the differences in amounts of certain volatile compounds such as hydrocarbons, aldehydes, alcohols and ketones [85]. On the other hand, the differences in meat flavors between bulls and heifers could be explained by the genetic control of animal development and production of sex hormones and their influence the lipid composition which affects the kinds of volatile flavor compounds [86]. Overall, it may be assumed that the differences in meat flavors existing between breeds or sexes are probably due to the differences in the levels of flavor precursors especially the fat contents which large affect the formation of aroma flavor compounds and also interact with other contents in determining flavor characteristics of cooked meat.
\n\t\t\tAgeing has been become a universal method widely used to improve eating quality of meat (e.g. tenderness, juiciness, flavor). Un-aged beef has a weak, bland odor while aged beef has a strong, savory, roasted odor. Ageing of meat makes an increase in fatty flavor characteristics however; long term ageing (e.g., > 3 weeks) could cause a decrease in positive flavor notes and increase liver-like aroma, bloody, bitter and off-flavor [87, 85, 88]. Ismail et al (2008) [89] stated that ethanol was responsible for the increase in alcohols caused by the microbial growth in beef during storage furthermore, the levels of aldehydes significantly increased after 7 days of storage. Beef from various muscles including gluteus medius, rectus femoris, vastus lateralis, vatsus medialis, teres major, complexus, serratus ventralis, psoas major and longissimus dorsi of heifer carcasses were chiller aged for 7 or 14 days the results showed that flavor-active volatiles included nonanal, 2,3-octanedione, pentanal, 3-hydroxy-2-butanone, 2-pentyl furan, 1-octen-3-ol, butanoic acid, pentanal and hexanoic acid which all often associated with lipid oxidation were affected by enhancement and ageing in the various muscles [90]. Additionally, ageing of beef achieved an increase in characteristic flavor and also aftertaste intensity, making an appreciable improvement of its flavor. After slaughter, loss of circulatory competency results in the accumulation of metabolic by-products, including lactic acid, in the muscle, that induces pH decline. The endogenous enzymes (e.g., cathespins B and L) are activated at near pH 5.4. Spanier and Miller (1993) and Spanier et al (1990) [91, 92] suggested that these thiol proteinases can hydrolyze more peptide bonds than any other group of enzymes, are redistributed during ageing period. Proteolytic enzyme activity is temperature-dependent; some enzymes retain high activity levels even at cooking temperatures. The combined effect of postmortem ageing and cooking, via enzyme redistribution and activity can influence the production of aroma flavor compounds. Toldrá and Flores (2000) [93] stated that enzymes known primarily for textural changes (e.g., μ- and m-calpain) during the postmortem period affect flavors by producing peptides, but it was observed that these enzymes correlate with increases in rancid, sour and salty flavors. The ageing conditions (e.g., oxygen availability, temperature, humidity and aging time) under which beef is aged influences the ultimate flavors of the meat particularly ageing in a higher oxygen environment cause a burnt, toasted off-odor. In addition, dry-ageing increases beef flavor attributes more than ageing in vacuum or in carbon dioxide [94, 95]. Based on the results reported in the previous studies it could be concluded that chiller ageing of meat resulted in increases of most of flavor compounds however a long ageing period (e.g., > 3 weeks) may negatively influences the flavor quality of cooked meat due to increase in amounts of some unexpected compounds which associated with undesirable flavors and decrease in the some important compounds which associated with desirable flavors.
\n\t\t\tCooking temperature is one of the important factors impacting the development of flavors through the Maillard reactions and lipid oxidation. Amino acids can undergo Strecker degradation to produce Strecker products. Degradation of sulfur-containing amino acids (e.g., cysteine, cystine and methionine) generates sulfur that contributes to subsequent processes of Maillard reaction. These compounds can react with amines and amino acids to produce a number of flavor-contributing compounds and potent cooked meat odorants such as pyrazines, oxazoles, thiophenes, thiazoles and other heterocyclic sulfur containing compounds [20]. It was well seen that cooking temperatures affect these reactions and then determine flavor characteristics, for instance the stewed meat lacks flavors of the roasted products because of stewed meat has a water activity of approximately 1.0 and not exceed temperature of 100oC while roasted meat has dried surfaces and temperature may exceed 100oC therefore, the conditions like low water activity and high surface temperature will increase production of flavor compounds which give roasted odor notes rather than meat is stewed. Ames et al (2001) [40] concluded that the amounts of most volatile flavor compounds increased with cooking temperature. Cooking at lower temperatures (<165 oC) versus higher temperatures (>180 oC) results in differences in the concentrations of a number of compounds such as 2, 4, 5-trimethyl- 3-oxazoline; 2, 4-dimethyl-5-ethyl-3-oxazoline; 2, 5- dimethyl-4-ethyl-3-oxazoline; 2, 4-dimethyl-3-thiazoline; 2, 4, 5-trimethyl-3-thiazoline [96]. Previous works found that a strong relationship existing between cooking temperature, concentration of free amino acids, carnosine, pyrazines and hexanol, and roasted, burnt and beefy flavor intensity [97, 98]. Cooking beef generates urea content which can also reduce sulfur-containing compounds generating important nitrogen-containing compounds like pyrazines and thiazoles in which pyrazines are formed mostly on the surface of meat and having nutty and roasty odor notes [99]. In general, the higher degree of heating, the higher the concentration of aliphatic aldehydes, benzenoids, polysulfides, heterocyclic compounds and lipid-derived volatiles. Ketones, alcohols sulfur-containing components make smaller contributions.
\n\t\t\t\tpH is one of the important factors that influence the kind of volatile flavor compounds formed in the Maillard reaction, and then determine the final flavor characteristics of cooked food. Madruga and Mottram (1995) [8] showed that as pH increases, color and polymeric compounds increase and nitrogen-containing compounds like pyrazines are favored, therefore it was assumed that higher ultimate pH in meat from grass-fed animals may favor the formation of thiazoles and thiophenones due to the availability of amino acid degradation products while decreasing other sulfur volatiles that favor lower pH. A number of early studies have been performed to investigate the effect of pH changes on volatile flavor compounds using model systems (El’Gde et al., 1966; Shu et
Irradiation is a food safety technology designed to eliminate disease-causing germs from foods. Depending on the dose levels of irradiation applying on the raw meat and poultry, or ready-to-eat meats that can eliminate bacteria commonly found such as E. coli, Salmonella and Listeria; virus; or parasites. However, irradiation may result in off-odors and flavors. The odors vary with the type of meat, temperature during irradiation, oxygen exposure during and/or after the irradiation process, packaging and presence of antioxidative substances [104]. Most of studies have reported that the aroma flavors of irradiated meat associated with rotten egg, sweet, bloody, cooked meat, barbecued corn, burnt, sulfur, metallic, alcohol, acetic acid, liver-like serumy and bloody [105, 106, 107]. Irradiation can initiate or promote lipid oxidation resulting in undesirable off-odors and flavors [108, 109]. Jo and Ahn, (2000) [110] showed that reactions of sulfur-containing amino acids with radiolytic products of water appear to be the source of hydrogen sulfide and other volatile sulfur-containing compounds which contribute to off-flavor. On the other hand, irradiation may result in the formation of free radicals from unsaturated fatty acids at double bond positions [109]. An increase in lipid peroxidation products such as hexanal and (E)-4,5-epoxy-(E)-2-decenal in combination with a loss of desirable meaty odorants (4-hydroxy-2,5-dimethyl-3(2H)-furanone and 3-hydroxy-4,5-dimethyl-2(5H)-furanone) result in development of warmed over flavor of cooked, refrigerated beef [16]. However, the effects of irradiation on aroma flavors are also depended on: (1) Dose levels of irradiation, it has been demonstrated that the dose levels of irradiation influence variedly on volatile flavor components of cooked meat, as reported by Jo and Ahn (2000) [110] who indicated some of hydrocarbons included 1-heptene and 1-nonene increased with irradiation dose immediately after irradiation of beef. A similar observation also was reported by Yong et al (2000) [111] who indicated that among the 150 flavor compounds indentified in beef the cyclodecene, (E)-2-hexenal, nonene and 2-nonenal showed an increase in a dose-dependent fashion. For the effect of irradiation on chicken flavors, Yong e al (2000) [112] showed that among the 129 identified volatile flavor compounds the cyclotetradecene, 2-methylpentanal and 4-methylcyclohexene were formed specifically in response to irradiation, and level of cyclotetradecene increased in a dose-dependent fashion; (2) Oxygen presence, the presence of oxygen around meats during irradiating can diffuse into the meats, and then results in radiolytic changes which precipitate oxidation and unacceptable secondary breakdown products. As well known, lipid oxidation needs oxygen presence to produce oxidized-products such as aldehydes, Nam and Ahn (2003) [113] indicated that irradiation of meat in aerobic packaging promoted production of aldehydes such as propanal and hexanal which is assumed as a good indicator of lipid oxidation. The similar observation also was reported by Nam et al (2001) [114] who also showed that irradiation increased TBARS values and off-flavor in aerobically-packaged pork (3) Temperature effect, temperature during irradiating meats has a large effect on aroma flavors of irradiated meat because temperature affects what radiolytic products are formed and what ratios [104]. Using lower temperature during irradiation of meat by freezing meat before irradiation can reduce detrimental effects via retarding autoxidation and extending shelf life; (4) pH effect, it has also been demonstrated that the ultimate pH of meat at the time of irradiation influences lipid oxidation. Nam et al (2001) [114] recently showed that irradiation increased lipid oxidation of normal and pale-soft-exudative (low pH group) muscles, whereas dark-firm-dry (high pH group) muscle was very stable and resistant to oxidative changes. Therefore, to minimize the detrimental effects of irradiation on aroma flavor characteristics we can modify atmosphere packaging by using vacuum packaging (anaerobic packaging) or replacement with inert gases (i.e. nitrogen, helium, hydrogen, carbon dioxide) to eliminate oxygen. Reducing the temperature (freezing) prior to irradiation and addition of antioxidants. Vacuum packaging retains irradiation-generated sulfur-containing compounds, however re-packaging meat in oxygen-permeable materials allows for dissipation of these flavor compounds.
\n\t\t\tWarm-off flavor and liver-like off flavor are undesirable flavors that result from the flavor changes and deterioration in meats that have been pre-cooked, chilled-stored and reheated. The warm-off flavor includes odors and tastes commonly described as stale, cardboard-like, painty, rancid, bitter and sour [115], and together with liver-like off flavor they both are the main factors that negatively affect eating sensory quality, purchase, economic impact of meat industry, and consumer complaint. Researchers have found that warm-off flavor appearing in cooked meat is mainly caused by oxidation of membrane phospholipids [116,115]. A recent report of Byrne et al (2001) [117], which also demonstrated that warm-off flavor associated with the development of lipid oxidation derived nuance off-flavor and odor notes such as rancid-like flavor and linseed oil-like odor, in association with a concurrent decrease in cooked pork meat-like flavor. The development of warm-off flavor usually results in loss of meaty flavor due to mask by lipid-oxidized products. Additionally, processes which involve any action that disrupts the muscle fiber membrane, such as chopping, restructuring, or heating which all can enhance warm-off flavor of meat product [118]. Previous works also suggested that reactions involving sulphydryl–disulfide interchanges in proteins and the degradation of sulfur-containing heteroatomic compounds, leading to a decrease in the ‘‘meatiness’’ of freshly cooked meat may also be an integral part of warm-off flavor [119,120]. For the liver-like off flavor of cooked meat, it was hypothesized that since foodservice preparation traditionally cooked the meat quickly and then held the product in warming ovens until the food was presented to the consumer these conditions might promote the liver-like flavor [27]. James and Calkins, (2005) [121] also hypothesized that the slower cooking and longer hold time allow the undesirable volatile flavor compounds to dissipate.
\n\t\tUp to present time, various techniques have been designed, combined with gas chromatography and mass spectrometry (GC/MS) or Flame ionizing detector (GC/FID) and applied to evaluate volatile flavor components in cooked meat. Of which, simultaneous steam distillation-extraction (SDE), dynamic headspace entrainment on Tenax TA, and solid-phase microextraction (SPME) are the techniques widely used for the extraction of volatile compounds in cooked meat [19, 122, 123, 85, 90, 124, 18,125]. SDE is a simple technique which involves small volumes of solvent, efficient stripping of volatiles and quantitative recovery of many compounds. The sample is dispersed in water which is heated to boiling. The steam that is generated carries volatiles with it into a section of the apparatus where the steam condenses in the presence of extracting solvent vapor. The co-condensation of volatile-laden steam and extracting solvent results in an effective extraction of volatiles [123]. The Dynamic headspace entrainment on Tenax has been used in the studies regarding cooked meat volatile flavor compounds since the 1980s. This technique probably has been used more than any other aroma extraction technique for the analysis of meat aroma and continues to be widely used. The action mechanism of this technique involving purging the headspace of a sample with a purified inert gas (e.g., nitrogen or helium), followed by collection of the volatiles onto a trap containing a suitable adsorbent, which will retain the volatile analytes carried there by the purge gas. Finally, the volatiles of meat samples collected on this trap are desorbed onto a GC or GC-MS column using a modified injection port. In the recent years, SPME technique has been widely adopted and considered as an alternative to isolate volatile flavor components in cooked meat. In SPME, the needle is coated with an absorbent material (e.g. CAR/PDMS), is placed above the cooked meat samples. Volatiles will migrate from the sample matrix to the needle coating and be absorbed. Volatile components will then be desorbed from the needle coating by inserting the needle in GC injection port.
\n\t\t\tThe extraction techniques as mentioned above in combination with GC/MS or GSC/FID can help researchers to tentatively detect the volatile flavor compounds in experimented meat samples but it could not identify the aroma flavors or odor characteristics of detected compounds. It would be advantageous to combine two or more different techniques, such as gas chromatography (GC) and olfactometry, the combination of measuring odor notes is called gas chromatography-olfactometry (GC/O). Gas chromatography-olfactometry (GC-O) is a bioassay that measures human response to odorants separated by gas chromatography. The superior sensitivity and selectivity of human olfaction make GC-O a powerful and meaningful tool for flavor chemistry. In the recent year, GC-O is one of the main techniques which have been used to determine intensity of aroma (odor) characteristics of volatile compounds in cooked meat [15, 21, 125].
\n\t\tIn order to have a cooked meat product with its desirable aroma flavors as expectation of consumer, it is important to understand how aroma flavors are derived, the mechanisms by which flavor components are generated, and the factors affect formation of flavor compounds then determine the final aroma flavor characteristics of cooked meat. Regarding the effects of factors on aroma flavors of cooked meat and to minimize the detrimental effects it is suggested if increasing the polyunsaturated fatty acids (e.g. C18:3n-3, DHA, EPA) to increase nutritional benefits to the consumer by using fat-supplemented diets however the undesirable flavors may result. Because the breakdown products of these fatty acids have a shorter chain length therefore are more volatile and they affect meat flavors by interacting with the Maillard reaction results in reducing levels of meaty aroma compounds such as sulfur-substituted thiophenes. Therefore, diets, feeding regimes, welfare and management of animals should be taken into account. Cooking conditions such as temperature, holding time and cooking methods play an important role in determining the formation volatile flavor compounds. In general, it has been demonstrated that cooking meat at high temperature (by roasting, grilling) will produce better aroma flavor characteristics due to the important Maillard products are formed. In addition to the cooking effect, it is suggested that a slow cooking and longer hold time can allow the undesirable volatile flavor compounds to dissipate, thus reduce warm-off flavor. Irradiation of meat can eliminate pathogens however, off-flavor may result therefore, and to minimize the detrimental effect of this method we can lower temperature during irradiation of meat by freezing meat before irradiation. Modifying atmosphere packaging by using vacuum packaging (anaerobic packaging) or replacement with inert gases (i.e. nitrogen, helium, hydrogen, carbon dioxide) to eliminate oxygen in meat during irradiation are also the alternatives. Chiller ageing of meat should be applied to improve eating quality however should not age for a long time (3 week period in maximum is encouraged) because chiller ageing meat for a too long period may result in flavor deterioration and decreasing desirable flavors.
\n\t\tIdiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease of unknown etiology, progressive and irreversible interstitial lung disease (ILD). IPF is the most common form of idiopathic interstitial pneumonia. It affects around 3 million people worldwide [1]. The increasing count of IPF cases is evident. The prognosis for patients with IPF is poor, with a median survival of 3–5 years if untreated [1]. IPF generally affects adults over 50 years, mainly in their sixth or seventh decade, but the earlier onset was noted in familial IPF. According to the epidemiological data, the incidence rates in Europe and North America are between 2.8 and 19 cases per 100,000 people per year [2]. The number of cases older than 65 years of age is about 400 per 100,000. The IPF has a prevalence of 8.2 cases per 100,000 and belongs to the rare diseases group [3]. The first IPF manifestation is shortness of breath (up to 85% of cases), chronic non-productive cough (up to 75%), tiredness, loss of appetite, and progressive exertional dyspnea, followed by an impaired quality of life [4]. More rarely, it can be an acute exacerbation (AE), acute episodes of sudden, rapid worsening of the disease of dyspnea over just a few weeks, and a consequent significant increase in mortality risk [5].
The pathogenesis of IPF is not completely understood. For many years, IPF was principally an inflammatory disease, given the increase in inflammatory cells in the lungs. Dramatic advances in the understanding of IPF pathogenesis mechanisms over the past decade were based on proteomics data. It discovered proteins in terms of prognosis, diagnosis, and IPF progression. Today, we think about IPF as an epithelial-driven disease. IPF originates from unknown microinjuries resulting from recurrent exposures of the lung epithelium to stimuli or predisposition, followed by initiation of alveolar epithelial cells (AECs) dysfunction, fibroblast recruitment, and proliferation and progression of fibrosis through fibroblast differentiation, myofibroblasts proliferation, and accumulation of extracellular matrix and remodeling [6].
Usually, pulmonary function tests reveal reduced total lung capacity, low carbon monoxide diffusing capacity, and arterial hypoxemia. Although the course of the disease is variable, IPF has a poor prognosis, mortality is high, and reported median survival is from 2.5 to 5 years from the time of diagnosis [7, 8].
The most frequent cause of death is respiratory failure. Although there is no identified cause for the IPF, men are more frequently affected than women. Genetic and environmental factors may contribute to the development or worsen the prognosis of IPF. A history of smoking increases the risk of developing IPF. Occupational and environmental risk factors for IPF are agricultural exposure, dusts from metal, asbestos, wood, chemicals, air pollution, etc. Although IPF is a disease that is limited to the lungs, numerous comorbidities have been increasingly recognized in patients with IPF, such as cardiovascular, pulmonary hypertension and ischemic heart disease, gastroesophageal reflux, lung cancer, chronic obstructive pulmonary disease/pulmonary emphysema, depression, sleep apnea, and diabetes [9].
Diagnosis of IPF is challenging because the initial symptoms are vague, non-specific, often mild, and may be attributed to advancing age or other diseases. Frequently the diagnosis is complex, requiring a multidisciplinary evaluation as recommended by international guidelines. The diagnosis of IPF continues to be a diagnosis of exclusion of other known causes for pulmonary fibrosis. High-resolution computed tomography (HRCT) plays a central role in the diagnosis of IPF. The presence of the HRCT pattern of usual interstitial pneumonitis is the hallmark of IPF diagnosis. In the case of the inconsistent pattern of UIP, significant inter-observer variability, surgical lung biopsy is necessary despite possible complications: triggering of the pneumothorax, pulmonary collapse, etc. Specific combinations of HRCT patterns and histopathology patterns in patients subjected to lung tissue sampling (transbronchial lung cryobiopsy or surgical lung biopsy) are an important part of the diagnosis.
In summary, the required criteria for diagnosing IPF is the combination of exclusion of known causes of ILD and presence of UIP pattern on chest HRCT or exclusion of known causes of ILD and specific HRCT/histology combinations. In the case of atypical HRCT presentation, lung biopsy is recommended. However, not all patients are eligible due to age and comorbidity limits. The average time from the symptoms’ onset to the correct diagnosis is approximately 1.5 years [10, 11, 12].
Current guidelines also support the use of clinical, radiological, and physiologic evaluations to estimate IPF disease severity and predict disease progression [12]. These include quality of life questionnaires and quantitation of IPF exacerbation frequency; serial measurements of forced vital capacity (FVC), diffusing capacity for the lungs for carbon monoxide (DLCO), and 6-min walk test (6MWT) distances; and sequential HRCT scans when indicated. Composite scoring systems such as the Composite-Physiologic Index (CPI) and Gender Age Physiology (GAP) index, which incorporate demographic and physiological data, may represent more accurate prognostic models [13, 14].
IPF patients usually respond poorly to therapy. The treatment is based on the use of antifibrotic drugs (nintedanib or pirfenidone), which slow down the disease progression, but they do not significantly improve the survival of these patients. Lung transplantation is the only treatment option that increases survival in IPF. Early intervention may help improve clinical outcomes [15].
A growing body of knowledge highlights IPF diagnosis, and providing accurate prognostic information is difficult using the currently available clinical, radiological, and physiologic findings. Furthermore, pulmonary function tests, clinical assessments, and imaging are very good for some cases, but not good for others. For example, lung biopsy is often not feasible in an elderly population with co-morbidities, etc. [16].
With the development of new treatments for IPF, it is critical to identify patients at an earlier stage of disease and rapidly identify those patients who will progress to worse clinical outcomes. That’s why there has been an emergence of molecular biomarkers. Compared to today’s diagnostic methods, an optimal biomarker for discriminating patients with IPF from healthy subjects or non-IPF patients should be less invasive, more rapid, and reproducible, easier to obtain from patients.
At the same time, we are the witnesses that non-invasive biomarkers can provide very important information for the clinical assessment of patients. Although considerable advances have been made in the last decade in revealing IPF pathogenesis, this is not the case with IPF biomarkers. Similar to the previous guidelines, current existing guidelines such as 2021 German Respiratory Society (DGP), 2018 American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), American Latin Thoracic Association (ALAT) guidelines strongly recommend not to measure any serum biomarker for IPF diagnosis and distinguishing IPF from other interstitial lung diseases in patients with newly detected ILD of apparently unknown cause who are clinically suspected of having IPF. Also, no guidelines on prognostic biomarkers are available [12, 17, 18, 19, 20].
Although there is no molecular biomarker in widespread clinical use for IPF, advancements in this field have been achieved; a growing body of literatures indicates a fascinating field of IPF biomarkers has reported changes in the level of various biomarkers in IPF patients, which implies the potential to become a new tool for clinical practice of IPF.
IPF biomarkers include:
predisposition biomarkers for identification of patients at risk for developing IPF
diagnostic biomarkers for identification of IPF patients and differentiation of IPF patients from healthy controls or patients with other ILD or another lung disease
prognostic biomarkers for staging disease severity, monitoring disease progression, herald worsening of IPF or the onset of an acute exacerbation or more accurate prediction of mortality
therapeutic biomarkers that are a reliable measure of efficacy and safety during treatment
biomarkers used as a surrogate endpoint in clinical trials helping predict clinical benefit based on epidemiologic/therapeutic/pathophysiologic evidence [21, 22, 23].
It is very well known that the ideal biomarker should be noninvasive, easily measured by a single, readily available test, to have high sensitivity/specificity, to be reproducible, accurate, widely available, and cost/effective [24].
Before considering the clinical implementation of the biomarker candidate, it must be evaluated critically with respect to key analytical and clinical characteristics. Criteria to be satisfied for definitive clinical implementation of biomarker related to the test such as adequate assays for its measurement, its predictive value defined in specific clinical contexts, optimal cut-off(s), and known timing of measurement (release kinetics) [25, 26].
Biomarkers should be measured from body fluids or tissues (serum, urine, exhaled breath condensates bronchoalveolar lavage fluid (BALF) transbronchial biopsy, surgical lung biopsy, etc.) with a recommendation to use easily obtainable body fluids or tissues. Although airway biomarkers could be obtained non-invasively via exhaled breath, is simple to collect and unlimited in quantity, most studies used bronchoscopy to obtain these biomarkers via BALF [27].
Additionally, incremental marker value should be examined, and the data about the effect on patient management and outcome and cost-effectiveness should be available. Also, validation across sexes, ages, ethnicities, and disease severity to assure generalizability is very welcome.
This chapter will summarize our current knowledge about IPF biomarkers associated with alveolar epithelial cell damage and dysfunction, biomarkers related to extracellular matrix remodeling and fibroproliferation, as well as biomarkers related to immune dysfunction.
Markers that belong to this group are the most studied biomarkers and offer the most convincing data. The increase in serum levels of these markers can be attributed to an increase in the production of these proteins by regenerating alveolar type II cells and/or to an enhanced permeability following the destruction of the alveolar-capillary barrier [28].
Krebs von den Lungen-6 (KL-6) antigen is a high molecular weight glycoprotein belonging to the group of human transmembrane mucins, expressed on type II pneumocytes, bronchial epithelium, as well as in glandular epithelium, including breast and pancreatic epithelium [22].
It was originally studied as a potential tumor marker in adenocarcinoma, whereas today’s research is mainly based on KL-6 as a diagnostic and prognostic biomarker in ILD [22]. It shows marked inter-individual variability in serum levels.
Although few studies have revealed the KL-6 role as a diagnostic marker for IPF and found a higher value of KL-6 in patients IPF compared to controls. KL-6 was approved in Japan more than twenty years ago as a diagnostic biomarker in ILD [29].
Serum concentrations of KL-6 depend on the polymorphism of the MUC1 gene encoding its synthesis, which accounts for the different values in people of different ethnicities [29]. For these reasons, validation in the non-Asian population is necessary for this biomarker to be internationally used in patients with IPF [30].
However, KL-6 has been mostly studied as a prognostic biomarker. KL-6 values are predominantly increased in ILD, characterized by damage to AECs and progressive thinning of the interstitium, including IPF. A serum cut-off value of ≥1000 U/ml is associated with a poorer prognosis of patients with ILD and a higher risk of death [30].
KL-6 fluctuations in the follow-up of IPF patients have also been reported to be potentially useful in predicting functional disease progression [31]. Few studies examined the prognostic significance of serial measurements of KL-6 levels in IPF. Sokai et al. [32] found that serial measurements of serum KL-6 may provide additional prognostic information than physiological parameters in patients with IPF. Wakamatsu et al. [33] found that patients with both initial serum KL-6 values <1000 U/mL and no serial increase in KL-6 had more favorable prognoses than those with serial increases in KL-6 or initial serum KL-6 values ≥1000 U/mL. Bennett et al. [34] revealed that higher KL-6 levels in BALF are related to the more severe and extended disease.
As previously discussed, the course of IPF varies widely, and some patients experiencing acute exacerbations of IPF, but the risk factors contributing to AE are unclear. It was noticed that basal values of KL-6 are significantly higher in patients who develop AE compared to patients with stable IPF [30]. Qui et al. [35], in systematic review and meta-analysis, investigated the risk factors for AE in IPF patients. The meta-analysis included seven articles involving 14 risk factors for AE in IPF patients, and poor pulmonary function, mechanical procedures, higher serum KL-6, and secondary pulmonary hypertension were associated with increased risks of AE in IPF patients.
Meta-analysis of 10 studies in IPF found that KL-6 had the strongest association with diagnosis of lung fibrosis compared with the three other examined markers (SP-D, SP-A, and MMP7) until for prognostic studies (decline in forced vital capacity and/or mortality) in IPF, KL-6 showed significant prognostic value [36].
Recently published systematic review and meta-analysis [37] was evaluated the robustness of available evidence for the use of KL-6 measurements in blood to predict prognosis in IPF patients. Twenty-six studies were included in the systematic review, and 14 studies were mainly performed on Asian patients in meta-analysis. The meta-analysis found that IPF patients with increased KL-6 concentrations had a significantly increased risk of developing AE, but the relation of KL-6 concentrations with mortality was not found.
Secreted mucins are the most abundant glycoprotein component of mucus. Secreted mucins (MUC2, MUC5AC, MUC5B, MUC6–8, and MUC19) are secreted into the extracellular space [38] MUC5B is among the major best-described, secreted gel-forming mucins. The main tissues expression of MUC 5B is; respiratory tract, submandibular glands, endocervix. Mucin 5B is one of the main components of respiratory secretions, and it participates in defense of the respiratory system from infections [39, 40]. However, the accumulation of this gel-forming glycoprotein further contributes to impaired gas exchange and complicates the clinical features of IPF patients [41]. The over-expression of mucin 5B in a study in mice showed a negative effect on mucociliary clearance, so inhaled harmful substances remain in the airways longer and initiate damage, and consequently tissue repair with fibrotic changes [42].
In 2011, a genome-wide linkage study identified a locus on chromosome 11 that was significantly associated with IPF risk. A common single nucleotide polymorphism (SNP) (rs35705950) in the promoter of the gene encoding for Mucin 5B (MUC5B) is associated with an increased risk for IPF [43, 44]. Meta-analysis of Zhu et al. [45] revealed a strong association between the MUC5B promoter rs35705950 polymorphism and the risk of IPF, and confirmed that the minor T allele is significantly associated with an increased risk of IPF compared.
The same polymorphism has been associated with higher concentrations of MUC5B and its distribution, predominantly in the epithelial cells of small airways [46]. Mutations in this gene are not the only cause of increased mucin expression. Recent data indicate that increased DNA methylation is also associated with increased MUC5B expression [47]. This association has not been clarified yet and is certainly a topic for future research.
It was also shown that mucin 5B could be a good prognostic marker. Namely, the mutation in the promoter region of the MUC5B gene is associated with a lower risk of lethal outcome [48]. It has not yet been found how the same mutation leads simultaneously to an increased risk of disease. Yet, it is associated with a better prognosis and a higher degree of survival.
Certain similarities between IPF and lung cancer have already been identified. Both diseases primarily affect the lower parts of the lung lobes; risk factors such as smoking, exposure to harmful substances in the living and work environment, viral infections, and others are also common. There are also certain similarities in pathogenetic mechanisms, such as genetic and epigenetic changes, dysfunctions at the molecular and cellular levels, and activation of certain signaling pathways [49]. All the above indicates the possibility of using certain tumor markers in IPF when assessing the severity of the disease and predicting the outcome [50].
Carbohydrate antigen 19-9 (CA 19-9) is a marker of epithelial damage, widely used as a serum tumor marker of carcinoma of the pancreas and digestive system [51]. An increase in the concentration of this marker has been observed in patients with IPF, but the significance of determining it is still speculative.
Another widely used tumor marker that indicates the severity of the disease in IPF is CA 15-3. This glycoprotein, or the most significant tumor marker of breast cancer, is elevated in patients with pulmonary fibrosis. It is useful in predicting the severity of the disease, and after lung transplantation, there is a decrease in its concentration [50].
Carcinoembryonic antigen (CEA), a glycoprotein used as a serum tumor marker of colon, rectum, stomach, pancreas, lung, and breast cancer, also stands out as a useful marker in IPF [52]. The values of this analyte are elevated in IPF and are associated with the severity of the disease [52].
Yin and Lloyd [53] recently identified MUC16 as a transmembrane mucin corresponding to the CA125 antigen, long known as a marker for ovarian cancer. Recently, CA125 was identified as a serum biomarker for disease progression and death in IPF patients.
In the analysis from the PROFILE study, examining 123 serum proteins in IPF patients, Maher et al. [54] singled out primarily CA19-9, CA125, and SP-D as three markers with the greatest potential for routine use in clinical practice. Although these three biomarkers are all secreted in small amounts by the pulmonary epithelium in states of health, SP-D being secreted by alveolar type 2 cells and CA19-9 and CA-125 by the bronchial epithelium, they are secreted abundantly by the metaplastic epithelium of IPF patients. Mahler et al. [54] indicate that the potential of these parameters is reflected precisely in their ability to distinguish patients from healthy people (SP-D) reliably, predict disease progression (CA 19-9), and dynamically reflect disease progression and overall mortality (CA 125) [54]. By examining the concentrations of CA19-9 in the final stage of IPF, Balestro et al. [55] got results consistent with previous research. Namely, most patients at this stage of the disease had CA19-9 values above the threshold (37kU/L). As confirmed by the results of several studies on different populations, CA19-9 is a reliable marker of disease progression [50, 54, 55].
The direct mechanisms of the increase in the concentration of tumor markers in idiopathic pulmonary fibrosis remain unclear. Nevertheless, research results are consistent in that these already widely used markers are useful in assessing the severity and progression of IPF [49, 50]. The great potential of these molecules is reflected, among other things, in the fact that they are already in routine use, as well as that there are commercial tests for their determination, unlike many of the aforementioned potential markers of the IPF.
Surfactant proteins are lipoprotein complexes synthesized and then secreted exclusively by alveolar epithelial cells, bronchial epithelial cells, as well as Clara cells [56]. They are encoded by SFTPA, SFTPB, SFTPC, and SFTPD genes [57]. Their role is to reduce surface tension in the alveoli and prevent their collapse [58].
Surfactant proteins themselves, as well as mutations in the genes encoding these proteins, have been described as potential biomarkers in IPF [22]. Mutations in the genes for surfactant proteins (SP) C and A2 have been associated with the development of oxidative stress and damage to the endoplasmic reticulum, but an additional profibrotic stimulus is necessary to induce the development of pulmonary fibrosis [59, 60, 61].
However, SP-A and SP-D are the most studied surfactants in IPF, as well as surfactants studied for the longest time. The mechanisms by which SP-A and SP-D from pneumocytes enter the circulation are hyperplasia of AECs and thus increased synthesis of these proteins, and loss of AEC integrity i.e., increased permeability of the basement membrane of the pulmonary epithelium to the interstitium [58].
In the serum of patients with IPF, there was a significant increase in the concentration of SP-A and D, while in contrast, their concentration in BAL was lower compared to healthy, control subjects [58]. In addition, an increase in SP-D has been found in patients with acute exacerbations of the disease [62]. This surfactant protein may be useful in detecting patients who are more prone to disease progression and poorer outcomes [54]. There is evidence that SP-D is a biomarker that can be used for differential diagnosis of interstitial lung disease, as its level is higher in IPF than in other ILDs [63].
Wang et al. [64], in a meta-analysis of 21 articles, evaluated the use of serum SP-A and SP-D for differential diagnosis and prognosis of IPF. Serum SP-A levels were significantly higher in patients with IPF than in patients with non-IPF ILD. In the AE of IPF, serum SP-A/D was higher than those in the stable stage.
Studies, therefore, show that these proteins, as well as KL-6 and matrix metalloproteinase-7 (MMP-7), are predictive markers; however, in some studies, only SP-A and SP-D are independent predictors of mortality [65]. In addition, SP-D has proved to be a more sensitive marker than SP-A, with a sensitivity of 77% (SP-A sensitivity is 33%). However, these markers are not specific to IPF, but their increase is also observed in other interstitial lung diseases. Also, a study conducted in South Korea has shown that the application of these biomarkers in IPF, combined with clinical parameters, does not significantly contribute to the assessment of outcome compared to the application of clinical parameters alone. However, if KL-6 is included in the assessment, the contribution of biomarkers to clinical parameters becomes significant [65].
Compared with SP-A and SP-D in the serum of patients with IPF, the data for SP-B are limited. SP-B is a component of pulmonary surfactant, produced by alveolar epithelial cells, which is synthesized as a preproprotein [66]. The maturation process of this protein involves primarily the removal of the signal peptide, followed by the glycosylation of the C-terminal region, and finally, the cleavage of the N- and C-terminal propeptides [67]. Mature surfactant protein B is hydrophobic and strongly associated with phospholipids rich in surfactants. At the same time, its precursors, proSP-B, and C-proSP-B are more hydrophilic so that they can be found in the supernatant of bronchoalveolar lavage [68]. In healthy subjects, concentrations of both mature and SP-B precursors are almost undetectable in serum [69]. The study of Khan et al. [68] has been studied SP-B precursor, C-pro-SP-B, as a new biomarker in serum of patients with different chronic lung diseases, including ILDs. The highest C-proSP-B levels were detected in the serum IPF patients. In a multivariate analysis, C-proSP-B levels were able to discriminate IPF patients from patients with all other pulmonary diseases (p < 0.0001). SP-B pre-proteins might serve as a biomarker in pulmonary diseases with alveolar or interstitial damage in IPF.
Clara cells are exocrine bronchiolar cells with several different physiological functions, including a protective and regenerative role, as well as a role in maintaining pulmonary homeostasis [70]. These cells’ protective and regulatory function is achieved through the secretion of various surfactants, glycosaminoglycans, enzymes, and other proteins [70]. In addition, these cells are involved in the biotransformation of many harmful substances that enter the lungs through the inhaled air [71].
CC16 is a 16 kDa homodimeric secretory protein of Clara cells with anti-inflammatory and antioxidant properties and has been studied as a potential therapeutic agent in various lung diseases [70]. It is encoded by the SCGB1A1 gene. Low serum CC16 values are associated with decreased lung function in children, accelerated decline in lung function in adults, and an increased risk of death, primarily in lung cancer [72].
In contrast, significantly high values of CC16 have been observed in the serum and bronchoalveolar lavage of patients with IPF [72]. Also, CC16 values are high in other interstitial lung diseases, such as sarcoidosis, although the values are significantly higher in IPF [72]. It is assumed that the activation of Clara cells after the alveolar epithelium damage leads to elevated serum concentrations of CC16. However, the exact role of CC16 in the alveolar repair process has not been thoroughly tested [70]. Although CC16 is a potential biomarker in various lung diseases, further studies are needed since CC16 values do not correlate with disease severity; there are no reference values, nor can it be used independently in diagnostics since it is a non-specific marker [70].
Telomeres are repetitive nucleotide sequences at the ends of chromosomes, whose role is to protect chromosomes from degradation [73]. As DNA polymerase cannot completely replicate the DNA strand, wherein a sequence of about 50 nucleotides is lost during each replication, the importance of telomeres is reflected in the fact that during replication, these non-coding parts of chromosomes are lost. The loss of telomere parts is compensated by the telomerase enzyme, which incorporates guanine-rich sequences at the ends of chromosomes during cell replication. However telomeres become shorter during repeated replications, resulting in cell aging and apoptosis [74].
It has been found that approximately one-third of patients with familial IPF have shortened telomeres, and/or mutations in the gene encoding telomerases [75]. When examining telomere length in peripheral blood leukocytes in patients with IPF, it was found that 40% of patients with familial IPF and a quarter of patients with sporadic IPF have shortened telomeres, below the 10th percentile [76]. In a 2014 cohort study involving over three hundred patients with IPF, it was found that telomere length in peripheral blood leukocytes was an independent predictor of mortality [77]. It was also found that telomere shortening in peripheral blood leukocytes as a surrogate marker for telomere mutations, so telomere length in peripheral blood may be examined in the family of a carrier of these mutations, instead of carrying out genetic analysis, which would indicate a risk factor for familial IPF [78].
Integrins are receptors found on the surface of cells, and they have a role in their binding to the extracellular matrix, in the interconnection of cells, and their migration, proliferation, and innate immune response [79]. Structurally they are heterodimers, made of different α and β subunits, and the αvβ6 integrin itself consists of αv and β6 subunits. The β6 subunit is expressed only in epithelial cells, so the whole integrin is present only. This integrin is extremely important for the pathogenesis of IPF, as it can activate transforming growth factor beta (TGF-β), which is involved in the interaction of lung epithelial cells and fibroblasts [80]. In patients with IPF, higher concentrations of this integrin have been found in lung tissue [81]. Also, higher concentrations of integrin are associated with a poorer prognosis [82].
Matrix metalloproteinases (MMP) are zinc-dependent proteases, which degrade the extracellular matrix. They can modulate the proliferation, migration, and apoptosis of smooth muscle cells, endothelial cells, and some types of immune system cells. So far, 23 members of this family have been discovered, encoded by 24 genes, where two genes serve to encode the same matrix metalloproteinase - MMP-23 [83]. Under physiological conditions, the activity of these enzymes, collectively called matrixins, is regulated at the level of transcription, activation of their inactive zymogen precursors, interaction with extracellular matrix components, and finally inhibition by endogenous inhibitors [84]. Matrixins are divided into seven categories: collagenases, gelatinases, stromelysins, membrane-type MMP, matrilysins, metalloelastases, and other types of matrixins [85].
Although MMPs are expected to prevent fibrotic changes due to their many functions and role in ECM degradation, these enzymes can have both a profibrotic and an antifibrotic role [85]. More details on members of the MMP-7 and MMP-1 matrix families, specifically elevated in the serum of patients with IPF, will be provided below.
This metalloproteinase is expressed in alveolar epithelial cells, phagocytes, and fibrocytes. An increase in MMP-7 levels has been observed in patients with IPF, and this enzyme has been confirmed as a biomarker of IPF [86]. The expression of this matrixin in the lung epithelium in IPF is further increased by osteopontin, a marker that will be discussed later [87]. Two SNPs have been identified in the promoter of the MMP-7 gene, which causes increased transcription, and are associated with the development of idiopathic pulmonary fibrosis [88]. In addition, as an enzyme that effectively removes tissue pathway factor inhibitor (TPFI), MMP-7 creates a procoagulant environment in the alveolar space, which has been observed in many fibrotic diseases, including IPF. Although this enzyme is also involved in the regeneration of lung epithelium after damage, in studies in mice lacking the MMP-7 gene, it was not possible to induce pulmonary fibrosis (PF) with bleomycin, suggesting that this metalloproteinase nevertheless promotes the development of PF [89]. This fact singles out MMP-7 as a potential new therapeutic target.
White et al. study tested the differentiation of IPF from a heterogeneous comparator group that included various other ILDs [63]. In another study, the serum MMP7 levels of IPF patients were compared to a group of patients with other ILD. Serum MMP7 values had a median sensitivity, specificity, accuracy, and diagnostic odds ratio of 71.7, 64.4, 68.4, and 4.7%, respectively [90]. MMP7 indicates a correct IPF diagnosis in more than half of the patients, suggesting an incorrect classification in about one-third of patients. Based on these data, the diagnostic value of these serum biomarkers is currently considered insufficient to support clinical use [17].
The Bosentan Use in Interstitial Lung Disease (BUILD)-3 trial that assessed potential prognostic capabilities of few biomarkers showed that MMP-7 is higher than healthy controls. Baseline MMP-7 levels were good predictors of worsening and could predict changes in FVC as early as month 4. MMP-7 shows the potential to be a reliable predictor of lung function decline and disease progression [91].
Despite the promising data regarding MMP-7 as a prognostic biomarker of IPF, it is not included in clinical practice due to the lack of reproducible, uniform cut-off values in different studies. There are major discrepancies between different studies about collection matrices; for example, EDTA collection tubes suppress MMP activity while PBMC layers are sometimes [10% of cases) contaminated by neutrophils, therefore significantly affecting predictive cut-off thresholds [92].
This type of matrixin degrades the extracellular matrix collagen; it is not expressed in healthy tissue but during physiological and pathophysiological processes [87]. Along with MMP-7, MMP-1 is the most studied matrixin in IPF. The combination of these two matrixins in the diagnosis of IPF has a positive predictive value of up to 91% (for concentrations of MMP-7 > 2.6 ng/mL and MMP-1 > 8.9 ng/ mL). Additionally, elevated values of these two MMPs can reliably distinguish IPF from other ILDs [86].
Osteopontin (OPN) is an acidic phosphorylated glycoprotein secreted by various cells, including osteoclasts, activated T-lymphocytes, and activated macrophages [93]. Osteopontin is a multifunctional cytokine involved in various biological processes, including cell adhesion, chemotaxis, and reparative processes [87]. In this regard, the biological role of osteopontin in the pathogenesis of cardiovascular diseases, diabetes, glomerulonephritis, and several types of cancer is suggested [93, 94].
The function of osteopontin in the occurrence of pulmonary fibrosis was tested in experimental mouse models, where the role in promoting the migration, adhesion, and proliferation of fibroblasts in the bleomycin-induced pulmonary fibrosis was demonstrated [93, 94]. In addition, analysis of lung biopsy samples of patients with IPF showed that osteopontin is a cytokine with the highest expression [93].
Osteopontin serum values are significantly higher in AE of IPF, compared to values in stable IPF, which is associated with a poorer prognosis [87, 95]. Although OPN is increased in serum and BALF of IPF patients [96], it is not specific in differentiating IPF from other ILDs [93].
The studies did not show the correlation between OPN concentration and SP-A and KL-6 concentrations, which can be explained by the different origins of these markers. Serum values of KL-6 and SP-A better reflect a later phase of the fibrosis process, i.e., the remodeling phase [93]. Although OPN values are highest in patients with IPF, no significant differences were observed compared to the values in patients with other ILD subtypes, indicating the limited use of this biomarker in differential diagnosis [94].
Periostin is an extracellular matrix protein from the fascicline family, and it is involved in the pathogenesis of various diseases accompanied by increased levels of inflammation and fibrosis [97]. Studies have shown that periostin is a protein that is highly expressed in the lungs of patients with IPF [97, 98]. The highest level of periostin expression in the lungs is in fibroblasts, in the areas of active fibrosis [97]. Stimulation of periostin synthesis in fibroblasts is influenced by various factors, including TGF-β and IL-4/IL-13 [98]. Experimental mouse models have shown that suppression of the periostin gene or administration of neutralizing antibodies protects to a large extent against bleomycin-induced pulmonary fibrosis [99]. Also, periostin acts in cooperation with inflammatory cytokines, such as TNF-α, by activating NF-κB, which is accompanied by the production of inflammatory cytokines and chemokines, leading further to the development of pulmonary fibrosis [97].
All this indicates the importance of the biological role of periostin in the pathogenesis of PF. However, elevated serum levels of periostin are also observed in other inflammatory diseases, which is why there is a need to develop a test that will enable greater diagnostic specificity [98]. There is a test designed to determine specifically periostin monomers, which is a better diagnostic marker compared to total periostin [98]. In addition, both total and monomeric periostin are better predictive markers of short-term deterioration of IPF compared to conventional markers KL-6, SP-D, and LDH [98]. The potential role of periostin in the treatment of patients with IPF should also be noted since experimental mouse models have shown that suppression of periostin expression or administration of neutralizing antibodies may result in improvement in the fibroproliferative phase [99].
Lysyl oxidase (LOX) and lysyl oxidase-like proteins (LOXL) represent a group of enzymes with important roles in extracellular matrix remodeling, including covalent binding of elastin and collagen [100]. The LOXL proteins promote collagen accumulation and deposition, participating in ECM stabilization. In addition to the enzymatic function, LOX also has a function in regulating the transcription of elastin and collagen III genes [101].
Four LOX isoenzymes (LOX1-LOX4) encoded by genes located on different chromosomes have been identified [101]. Changes in LOX expression, i.e., increased LOX activity, have been associated with the mechanisms of fibrotic changes in certain lung, liver, and kidney diseases [101]. Increased LOX expression was observed in experimental mouse models in bleomycin-induced pulmonary fibrosis [101].
Also, elevated serum concentrations of LOXL2 in patients with IPF have been associated with a higher risk of disease progression but cannot be correlated with disease severity [101, 102]. Given its role in the pathogenesis of pulmonary fibrosis, the applicability of LOXL2 as a potential therapeutic target was examined. However, the study of the use of a monoclonal anti-LOXL2 antibody (simtuzumab) in the treatment of patients with IPF was discontinued in the second phase of the clinical trials due to the lack of efficiency [101]. One of the potential reasons for failure is the impossibility of adequate penetration into the lung tissue, but there were not enough data for a complete evaluation [101]. In any case, further testing of the diagnostic, predictive and prognostic value of LOXL2 as a biomarker in IPF is necessary.
IGFs are hormones or growth factors primarily synthesized in the liver. For the most part, they are bound to some of their binding proteins (IGF-BP), which modulate their effects and bioavailability [103]. The IGF binding protein family consists of six members, which also originate primarily from the liver. IGF and IGF-BP are synthesized locally in many tissues to achieve their autocrine and paracrine effects, respectively [104].
Studies have shown a significant increase in circulating concentrations of these binding proteins in newly diagnosed IPF patients. In contrast, in those patients who started using antifibrotic drugs, lower levels of GFBP-2 were found than in patients who do not receive this type of therapy [105]. IGFBP-2 values do not return to the levels of healthy subjects, even with the use of antifibrotic therapy [105].
As IGFs are very strong growth factors, their significant increase in the process of fibrosis, and even lung fibrosis, is expected. However, Guiot et al. [105] found a decrease in the concentration of these analytes in the serum of IPF patients. These surprising results can be explained in several ways. It is possible that IGF-BP, by binding to the extracellular matrix in the lungs with fibrotic changes, locally releases IGF and thus enables its effects in such an environment. On the other hand, an increase in the concentration of binding proteins to insulin-like growth factors means that these factors bind to a greater extent, thus reducing their effectiveness, which can also have a protective role in IPF [106, 107, 108].
Fibulin 1 (Fbln1) is a secretory glycoprotein with a significant role in embryonic morphogenesis and alveolar septal formation [109]. Four isoforms of this protein (Fbln1a/b/c/d) have been isolated, differing from each other in C-terminal sequences [110]. However, the identification of individual variants is difficult due to the unavailability of antibodies specific to certain isoforms [111]. Fbln1 has an important role in tissue repair and has been associated with several different respiratory diseases [111]. The importance of the Fbln1c form in the pathogenesis of various respiratory diseases is especially emphasized, which is achieved through the stimulation of fibroblast proliferation and remodeling of the extracellular matrix [110, 111]. Experimental mouse models have shown that the inhibition of Fbln1c expression reduces the proliferation of smooth muscle cells and fibroblasts and collagen deposition around the small airways [111]. In addition, mouse models have shown a significant role of Fbln1c in chronic inflammation, where the inhibition of Fbln1c expression reduces the influx of inflammatory cells into the bronchoalveolar lavage and the synthesis of cytokines and chemokines in the lungs [111]. Accordingly, Fbln1 is mentioned as a potential biomarker and therapeutic target in respiratory and other diseases involving inflammation and remodeling [111].
Elevated values of Fbln1 in the serum and lungs of patients with IPF compared to healthy subjects suggest a role of Fbln1 in the pathogenesis of this disease [109]. High values of Fbln1 in the lungs are a consequence of increased production in smooth muscle cells and fibroblasts; apart from that, under the influence of TGF-β, exogenously synthesized Fbln1 is incorporated into the extracellular matrix [111]. The high serum concentration of Fbln1 correlates with decreased lung function and is associated with acute exacerbation of the disease [109, 112]. Fbln1 values are higher in patients with IPF compared to other ILDs. Still, they are in correlation with pulmonary function in other types of disease, suggesting that Fbln1 may be a predictive marker of disease progression in other ILDs, such as idiopathic nonspecific pneumonia [109].
Excessive deposition of the extracellular matrix is critical to the pathogenesis of IPF. Collagen is the main component of the extracellular matrix, whose synthesis and degradation take place in a balanced way in healthy lungs, while in IPF, this balance is disturbed [113, 114]. During synthesis, the procollagen is cleaved, and during the degradation of collagen molecules, MMPs cut parts of this molecule, which reveals different neoepitopes in all these processes [115].
Peptides formed during synthesis and newly formed neoepitopes are released into the circulation and detected in the blood. Studies have shown that serum concentrations of neoepitopes of collagen synthesis PRO-C3 and PRO-C6 (collagen type 3 and type 6) are higher in patients with IPF compared to healthy subjects of the same age. Their elevated concentration is associated with IPF progression [115]. The concentration of collagen degradation markers (C1M, C3M, C6M, and CRPM) is also elevated in IPF. Longitudinal changes in serum concentrations of these neoepitopes follow the progression of fibrosis and can predict mortality in individuals with IPF in three months [116]. Biomarkers of collagen synthesis and degradation have the potential to improve clinical trials in IPF, prognostic evaluation, and make decisions on therapy [115].
HSP47 is a protein necessary for the synthesis and secretion of collagen molecules. Increased expression of HSP40 is closely related to excessive production and accumulation of collagen, so these data indicate a significant role of this molecule in fibrotic processes and its correlation with the activity of such diseases. It has been shown that a significant increase in the concentration of HSP47 occurs during the acute exacerbation of the disease, compared to the stable form of IPF. Additionally, this biomarker has been found to be superior to better known and studied markers of pulmonary fibrosis, such as KL-6 and SP-A and D [117]. It was assumed that, as HSP47 concentrations in the exacerbation phase of the disease are higher than during stable disease, this distinction would also exist between patients with a stable form of the disease and healthy subjects. However, these assumptions have been refuted in the research conducted [117, 118].
The precise role of HSP47 in the pathogenesis of IPF has not been determined, but this molecule is likely responsible for the additional effect of pirfenidone in the inhibition of fibrotic processes. In addition to direct suppression of type I collagen expression, it is possible that pirfenidone partially achieves its anti-fibrotic effect by suppressing the expression of HSP47 depending on TGF-β1 [119].
The lungs are characteristic of IPF patients in the regions of the so-called fibroblast foci, where ECM production is most active. In these foci, the predominant cells are myofibroblasts, where under the effect of various cell mediators, the proliferation of these cells takes place, with the inhibition of their apoptosis [120]. Myofibroblasts are cells that phenotypically correspond to the stage between fibroblasts and smooth muscle cells [121].
There are two hypotheses on the origin of myofibroblasts: traditional – that they are formed from fibroblasts after their activation by inflammatory stimuli and more recent – that they are formed by differentiation of alveolar epithelial cells [122].
Fibrocytes are cells originating from the monocytic lineage. In case of tissue damage, migrate to the site of damage attracted by chemotactic factors and then differentiate into fibroblast-like cells. They are present in the circulation and can produce ECM. Fibrocytes express different markers, and these are primarily CD45 leukocyte markers and type I collagen. During its differentiation, it has been found that CD45 expression gradually decreases while type I collagen expression remains unchanged. It has also been found that their differentiation is accelerated under the effect of TGF- β [123]. Although they have a protective role in the process of tissue remodeling and damage repair, it is considered that fibrocytes are involved in the progression of pulmonary fibrosis. Studies show that in the blood of IPF patients, an increased number of circulating fibrocytes is associated with a poor disease outcome [124, 125]. It has been found that, compared to healthy subjects, in patients with IPF, there is a significantly higher number of circulating fibrocytes, identified precisely as CD45+, collagen type I+ cells. In addition, in patients with AE of the disease, these cells are present in ten times greater numbers than in the case with a stable state [125].
Although IPF is primarily not an inflammatory disorder, inflammatory and immune-mediated pathways are activated in IPF patient’s lungs.
CC chemokine ligand 18 (CCL18) is a protein secreted by myeloid lineage cells: monocytes, macrophages, and dendritic cells. In patients with idiopathic pulmonary fibrosis, alveolar macrophages produce large amounts of CCL18 [126, 127]. Th2 cytokines lead to alternative activation of alveolar macrophages, which thus activated have a role in tissue and fibrosis healing [128, 129]. Alternatively, activated macrophages produce CCL18, which leads to increased collagen production by pulmonary fibroblasts, and collagen then stimulates alveolar macrophages to produce CCL18 by a positive feedback loop. In this way, the process of fibrosis is continuously maintained [126].
Increased serum concentrations of CCL18 in IPF are negatively correlated with pulmonary function tests and associated with disease progression [126, 127]. In a prospective study of 72 patients, significantly higher mortality was observed in the group of patients with a CCL 18 concentration above 150 ng/mL [130]. It was also found that pirfenidone used in the treatment of IPF significantly reduces the expression of CCL18 in macrophages [130].
Data obtained from meta-analysis Elhai et al. showed that CCL18 has a significant prognostic value [36]. Based on previous research, it can be concluded that CCL18 is a good prognostic marker in IPF.
In a posthoc analysis of phase 3 ASCEND and CAPACITY trials [131], concentrations of IPF biomarkers in IPF patients who received pirfenidone 2403 mg/day or placebo were investigated, and their associations with changes in FVC and disease progression over one year. CCL18 was consistently prognostic for absolute change in percentage of FVC% and was the most consistent predictor of disease progression across IPF cohorts.
CC chemokine ligand 2 (CCL2) is one of the chemokines involved in the recruitment of mononuclear phagocytes, thereby promoting inflammation and the development of tissue fibrosis [132]. Additionally, the recruitment of fibrocytes into the lungs most likely occurs because of interactions between chemokine ligands (including CCL-2) and their receptors [133]. More than 20 years ago, it was established that significantly higher serum concentrations of this chemoattractant are present in patients with idiopathic pulmonary fibrosis [134]. A recently published paper, which focused on examining the prognostic potential of various chemokines, found significantly higher concentrations of CCL-2 in patients with both acute exacerbations of IPF and a stable form of the disease, compared to a control group of subjects [135]. The same study concluded that CCL2 levels, among other chemokines, showed neither correlation with lung function nor patient survival [135].
CXC chemokine 13 (CXCL13) is a protein secreted by dendritic cells and the main mediator in attracting B lymphocytes to inflammatory lesions. Antigen-stimulated B lymphocytes undergo a process of gradual maturation, so these cells, as well as altered, differentiated B lymphocytes, are present in patients with IPF [136]. Increased CXCL13 mRNA has been isolated in the lungs of patients with IPF compared to control subjects, and serum levels of CXCL13 were increased in patients with IPF compared to control subjects. Elevated CXCL13 protein levels are associated with increased mortality in patients with IPF. The highest levels of CXCL13 were found in IPF patients with acute exacerbations or pulmonary hypertension [137].
The toll-like receptor is a transmembrane glycoprotein receptor expressed predominantly endosomal. Recent studies show an association between Toll-like receptors and aberrant fibrogenesis characteristic of idiopathic pulmonary fibrosis [138]. These receptors recognize molecular patterns that can be potentially dangerous and promote adequate immune response [138]. The Toll-like receptor 3 L412F polymorphism is associated with defective TLR3 activation, which causes mortality in IPF [139]. The association of this mutation with accelerated decline in lung function and consequent early death has been proven. This information can be critical in identifying patients with a rapidly progressive phenotype [140]. Toll-like receptor 3 belongs to the group of receptors that have a significant role in innate immunity. It mediates the innate immune response to tissue injury or infection by inducing NF-κB activation and type 1 interferon production [141]. Toll-like receptors recognize patterns from bacterial, viral, protozoal, and fungal pathogens, which are most important for their survival [141]. The Toll-like receptor 3 is a receptor that recognizes viral double-stranded RNA (dsRNA) and regulates the pro-inflammatory response and IFN-1 production [142]. In studies on fibroblasts in IPF, the unregulated proliferation of primary fibroblasts was observed and decreased production of IFN-β mediated by TLR3 receptors [139]. Activation of TLR3 receptors in primary fibroblasts has an antifibrotic effect and leads to a decrease in TGF-β production, increased collagen production, and increased metalloproteinase activity [143, 144].
The TLR signaling pathway during the reactive response to viruses acts as a blocker of fibroproliferation, so TLR3 signaling deficiency can cause an inadequate lung response to viral pathogens and expose them to chronic cycles of damage and repair considered the basis of IPF pathology [144].
Toll-interactin protein (TOLLIP) is a protein whose expression in the lungs has been observed in type II alveolar cells, macrophages, and basal cells. This protein has a role in important signaling pathways associated with lung diseases, including IL-1β, IL-13, TLR, and TGF-β [145].
It has been found that the rs111521887 and rs5743894 gene variants located in TOLLIP introns are associated with 40–50% reduced TOLLIP gene expression in the lungs and susceptibility to IPF [146]. Interestingly, the rs5743890_G allele is related to increased mortality in IPF, although it is associated with decreased IPF susceptibility, which suggests that the genetic basis is related to different clinical outcomes [39]. This indicates the heterogeneity and complexity of the pathogenesis of IPF [146]. TOLLIP is an important regulator of innate immune responses mediated by Toll-like receptors and the TGF-β1 signaling pathway through TGF-β1 receptor degradation [92]. It antagonizes the TGF-β signaling pathway by degrading the TGF-β1 receptor [147]. This TLR inhibitory protein is potentially useful for detecting various responses to the treatment of IPF in different genotypes [148].
Decreased TOLLIP expression increases proinflammatory cytokines IL-6 and TNF production in macrophages after TLR stimulation [149]. These data suggest that TOLLIP expression may be protective by reducing the proinflammatory and profibrotic cascade [144].
Defensins are small antimicrobial peptides mainly secreted by neutrophils and epithelial cells, which affect some gram-positive and gram-negative bacteria, as well as viruses [92]. Comparative analysis of gene expression from blood and lung tissue samples of patients with stable IPF and those with acute exacerbation of IPF revealed increased gene expression for alpha-defensins 3 and 4 in IPF with acute disease exacerbation [150].
Alpha-defensins are activated by MMP7, whose gene expression is also increased in the lungs of patients with IPF [22]. It has been found that serum levels of alpha defensin are higher in patients with IPF than in healthy subjects and are associated with the deterioration of the disease [150, 151].
S100 calcium-binding protein A4 (S100A4, fibroblast-specific protein-1) belongs to the S100 family containing calcium-binding motifs. S100A4 promotes lung fibrosis via proliferation and activation of fibroblasts and promotes the transition of fibroblasts to myofibroblasts [152].
Akiyama et al. [153] have shown the clinical significance of serum S100A4 in IPF patients. They revealed an independent association of higher S100A4 levels with a higher disease progression rate and a higher mortality rate, suggesting that S100A4 may be promising in the prognosis and management of IPF. The presence of higher levels of S100A4 in the serum of participants with IPF was linked with a significantly lower progression-free survival and higher 2-year mortality.
S100A8/A9 belongs to the S100 family of calcium-binding proteins derived from neutrophils and monocytes, which modulate the immune response [154]. In the pathogenesis of pulmonary fibrosis, the role of these proteins is based on the proliferation of fibroblasts, the influence on their differentiation, and the increase in collagen production by mentioned cells [155]. Concentrations of S100A8 and A9 are, as recent research results show, significantly higher in patients with acute disease exacerbation than in healthy patients, as well as in patients with confirmed IPF without acute exacerbation [156]. Patients with higher concentrations of these two biomarkers had a significantly poorer three-month survival rate, so S100A8 and S100A9 proved to be significant prognostic markers [156].
S100A12 is a member of the S100 family of calcium-binding proteins that has a significant role in regulating inflammatory processes and immune response. Its proinflammatory activity includes chemotaxis and activation of the intracellular signaling cascade, leading to cytokine and oxidative stress production [157]. In a study with a relatively large number of patients with IPF, serum concentrations of S100A12 in IPF were high and correlated with poor disease prognosis [158].
HSP production is regulated by various stress effects on cells, as well as their damage. They are located on the cell surface and have a role in transmitting information and modulation of the immune response [159]. Various autoantibodies to HSP have been found in patients with autoimmune diseases. What singled out HSP and autoantibodies to these proteins as potential biomarkers in IPF is, inter alia, the fact that cell cultures have been found to have the ability to activate monocytes and increase IL-8 production by these cells [158, 160]. IL-8, as a pro-inflammatory chemokine, further acts as a chemoattractant on neutrophils and activates them [161]. This interleukin is considered one of the major mediators in the pathogenesis of IPF, and its higher serum concentrations and BAL of these patients are associated with more extensive pulmonary fibrosis [162].
The results of a study conducted by Mills et al. indicate that IPF patients did not show a significant increase in serum antiHSP-72 antibodies compared to healthy subjects, nor did the concentration of the identical immunoglobulins differ between IPF and other interstitial lung diseases. However, in the bronchoalveolar lavage, an increase in the concentration of total antibodies (classes G, A, and M), but not of class G itself, is associated with a better disease outcome, i.e., it was observed in patients with slower disease progression [163]. These results contrast with the data from the previous study, which showed that the increase in the concentration of autoantibodies to HSP-70 in IPF patients was associated with a poor disease outcome [164]. This discrepancy in the conclusions can be justified by applying different methods, i.e., the antigens used to isolate antibodies and the non-homogeneous groups in the research of Kahloon et al. in terms of age, gender and ethnicity. It is undeniable that these proteins and autoantibodies directed at them have their place in the pathogenesis of IPF, but further research is needed to elucidate the role and potential use of these biomarkers in pulmonary fibrosis.
YKL-40 is a glycoprotein, a member of the chitinase and chitin-like protein family, expressed in many tissues, especially those characterized by high metabolic activity [165]. The exact biological role of YKL40 is not fully known, but it is involved in various pathophysiological processes as an inflammatory glycoprotein, including cell proliferation, migration, and tissue remodeling [166].
YKL-40 is mainly expressed in alveolar epithelial cells and macrophages, and its values are elevated in the serum and lungs of patients with IPF [165]. In addition, high concentrations of YKL-40 are detected in other diseases accompanied by high levels of fibrosis, such as liver cirrhosis, Crohn’s disease, and systemic sclerosis [165]. Elevated levels of YKL-40 in serum and bronchoalveolar lavage are associated with a higher risk of death in patients with IPF, although there is a weak correlation between these concentrations [104]. Also, YKL-40 values are inversely related to lung function in asthma, sarcoidosis, and IPF [165]. YKL-40 is not a marker specific for IPF, although the cut-off value of 79 ng/ml is mentioned in the literature and associated with a poorer prognosis [105]. Compared to the short-term prognostic markers SP-D and CCL18, YKL-40 has the highest predictive value 3–4 years after diagnosis, so a potential combination of these markers could allow a better assessment of survival [165].
Vimentin is a cytoskeleton protein in cells of mesenchymal origin which is considered responsible for increased cell invasiveness so that one can assume its importance in fibroblast invasion into the so-called fibrous foci in the lungs of IPF patients [167]. This filament is essential to the process of wound healing, so its overexpression results in increased cell invasiveness and excessive scar tissue formation [167, 168].
Immunochemical staining of tissue samples from IPF patients showed that vimentin was significantly more expressed in the cells at the periphery of the fibrous focus than in the center. In the same study, it was found that in the fasting state, as an inducer of the autophagy process, fibroblasts originating from IPF patients expressed vimentin more than control group fibroblasts, while the process of autophagy was lacking [169].
The defect of the autophagy process has already been associated with the development of idiopathic pulmonary fibrosis, where there is no removal of parts of the extracellular matrix by their implementation in autophagosomes and the destruction of these products after fusion with lysosomes [170, 171].
The antiangiogenetic, as well as the antitumor agent WFA (withaferin A), can bind to vimentin, covalently modify it, and cause its aggregation [172]. Treatment of IPF fibroblasts with this agent increased the number of autophagosomes in these cells, i.e., it stimulated autophagy. In addition, the expression of vimentin and type I collagen were reduced, and the inhibition of vimentin reduced the invasiveness of fibroblasts [169]. All these facts confirm the role of vimentin in pulmonary fibrosis and its importance in the progression of the disease.
Various cells involved in the development of pulmonary fibrosis secrete vimentin under the influence of TGF-β1 [173]. This secreted cytoskeletal protein was found in significantly higher IPF patients than in the healthy, control group [174]. Over-expression of otherwise immunologically inert molecules leads to their higher immunogenicity [175]. This is confirmed by the results of a 2017 study that proved anti-vimentin autoantibodies in IPF patients in a much higher concentration than is the case with other lung diseases and healthy subjects. Patients with poorer clinical and poor disease outcomes had higher circulating concentrations of anti-vimentin antibodies features [174].
As mentioned above, the central event in the development of IPF is an excessive reaction to repeated damage to alveolar epithelial cells with the formation of scar tissue that replaces the functional one [176]. Pulmonary fibrosis was considered a non-immune disease, but more and more evidence speak in favor of the role of the immune system in initiating the onset of fibrotic changes, as well as in the progression of fibrosis.
Regulatory T-lymphocytes are CD4+ T-cells that participate in immunosuppression and prevent the development of an immune response to the body’s antigens (autotolerance) [177]. These cells can produce various cytokines, including IL-10 and TGF-β1, and therefore may have the potential to both suppress and promote the onset of fibrotic changes [148].
Activation of these T-lymphocytes increases the expression of semaphorin seven, which has a chemotactic effect on macrophages, stimulates the production of proinflammatory cytokines, and regulates collagen production by fibrocytes [178]. Increased expression of semaphorin seven on regulatory T cells has been found in IPF [179].
The cell population of Th2 lymphocytes (T-helper cells) and their product IL-13, which have long been known to have a role in allergic diseases and the pathogenesis of asthma, are now also associated with the development of IPF. Namely, this interleukin affects the extracellular matrix production and induces tissue fibrosis, which has been shown in animal models, where increased expression of IL-13 had profibrotic effects [180]. Studies show an increased concentration of this cytokine in the blood of patients with IPF and the correlation of these concentrations with disease progression [181]. These claims are consistent with the results of studies performed on mice lacking the IL-13 gene in which the induction of pulmonary fibrosis by bleomycin was inhibited [182].
The soluble receptor for advanced glycation end-products (sRAGE) acts as a decoy for capturing advanced glycation end-products (AGEs) and inhibits the activation of the oxidative stress and apoptotic pathways. The study of Manichaikul et al. [183] found that adults with IPF have lower sRAGE levels. They were associated with greater disease severity and a higher death rate or lung transplant at one year compared with healthy controls. Additionally, lower plasma sRAGE levels in patients with IPF and other ILDs when compared with healthy controls Lower sRAGE levels were associated with disease severity. In their study, Cabrera Cesar et al. [184] provide evidence, for the first time, for the possible use of AGE as a differential diagnostic biomarker to distinguish between IPF and connective tissue disease-associated interstitial lung disease (CTD-ILD). The role of RAGE in human and experimental models of IPF did not fully understand [185].
Machahua et al. [186] evaluated the AGEs, and sRAGE levels in serum as a potential biomarker in IPF, demonstrate that the increase of AGE/sRAGE ratio is higher in IPF. AGE/sRAGE increase correlates with respiratory functional progression (FVC and DLCO values); changes in serum AGEs and sRAGE correlated with % change of FVC, DLCO, and TLC during the follow-up.
No difference in AGE or RAGE expression was observed in lungs with non-specific interstitial pneumonia compared to that in the controls. Levels of circulating AGEs also increased significantly in the lungs of patients with IPF compared to those with NSIP and normal control [187].
Aberrant angiogenesis is implicated in the pathogenesis of pulmonary fibrosis, and mediators of this process are VEGF, endothelin 1, interleukin 8.
Vascular endothelial growth factor-A (VEGF-A) is the predominantly expressed member of the VEGF family and is often denoted as VEGF. It is a tyrosine kinase glycoprotein and is one of the most potent factors that stimulate angiogenesis. VEGF is elevated in IPF compared with healthy controls [137, 188].
Barratt et al. [189] report that the levels of VEGF-A165b protein were found to be dramatically elevated in the lung tissue of patients with IPF, is produced mostly by the alveolar epithelium but also by macrophages, lymphocytes, and fibroblasts.
Ando et al. reported reduced VEGF-A in the BALF of IPF patients compared to controls [190]. VEGF-A levels in peripheral blood are associated with the severity and progression of IPF [191]. Enhanced expression of VEGF-A is correlated with increased alveolar-capillary density in non-fibrotic regions of IPF lungs [192].
Nintedanib, therapeutics for IPF, acts by targeting VEGF receptor signaling, slows IPF progression, but the utility of VEGF as a marker of treatment success is not determined [193, 194].
Endothelin-1 (ET-1) is a vasoactive peptide that plays a central role in lung fibrosis. ET-1 drives fibroblast activation, proliferation, differentiation into myofibroblast - processes that lead to excessive collagen deposition [195]. Barlo et al. [196] revealed that ET-1 in serum was significantly increased in IPF patients compared with healthy control subjects until it was significantly decreased in bronchoalveolar lavage fluid (BALF).
Interleukin-8 (IL-8) is produced by phagocytes when exposed to inflammatory stimuli and promotes angiogenesis [191]. IL-8 levels were significantly higher in IPF exacerbated patients, and an increase in IL-8 by one pg/ml increases the odds of death by 6.7% in IPF patients [197]. Schupp et al. [198] found significantly higher levels of IL-8 in BAL samples from IPF-AE patients compared to stable IPF patients. Xaubet et al. [199] found that the percentage of IL-8–positive bronchoalveolar lavage macrophages was significantly higher in areas of IPF lung with extensive fibrosis defined by HRCT scans compared with BALF from healthy volunteers.
The literature supports the concept of combining multiple markers and/or clinical parameters in clinical decision support. Biomarker panels consisting of two or more suspected biomarkers may potentially indicate a higher likelihood of IPF than any single biomarker, more effectively differentiate IPF patients from healthy volunteers and patients with other pulmonary diseases, define prognosis at the time of diagnosis, identify responses to therapy.
For example, the improved predictive value of the combination of biomarkers SP-A and SP-D in IPF was observed [200]. Rosas et al. [86] found that the combination of serum MMP1 and MMP7 levels distinguish IPF from other chronic lung diseases more than either protein on its own. Also, the combination of five proteins (MMP-7, MMP-1, MMP-8, Insulin-like Growth Factor Binding Protein 1(IGFBP1) and tumor necrosis factor receptor superfamily, member 1a (TNFRSF1A)) could distinguish with high sensitivity and specificity IPF patients from normal controls. White et al. [63] showed that a combined serum biomarker panel combining SP-D, MMP-7, and osteopontin differentiated IPF patients from other types of ILD (except for rheumatoid arthritis–associated ILD) more readily than each biomarker, and this biomarker index may improve diagnostic confidence in IPF. Hamai et al. [201] found that a combination of MMP-7 and KL-6 potentially support the diagnosis of IPF and might improve survival prediction in patients with IPF. Recently published study Xue et al. [202], found that KL-6, CCL3, and CXCL13 significantly improves the diagnosis of idiopathic interstitial pneumonia. IPF patients with a high level of SP-D but low KL-6 in their serum had a better prognosis [203]. A panel of mi-RNAs including miR-302c, miR-423, miR-210, miR-376C, and miR-185 has been shown to be associated with disease severity, differentiating fast from slow IPF progressors [204].
The next step was to examine the combination of clinical parameters and molecular biomarkers to achieve more accurate results regarding the prognosis of IPF. Kinder et al. [84] reported on a significant improvement in their prediction model of 1-year mortality in surgical lung biopsy-proven IPF, when serum levels of SP-A and SP-D were added to the clinical predictors of mortality alone [205]. Richards et al. [206] evaluated a panel of 92 proteins in a retrospective derivation cohort of IPF patients and tested significant findings in an independent validation cohort of IPF patients, and identified five biomarkers (MMP-7, intercellular adhesion molecule-1, Interleukin-8, vascular cell adhesion protein −1, S100A12) associated with disease progression or mortality. Combining clinical parameters and plasma protein concentrations (gender, FVC%, DLCO%, MMP-7), they constructed peripheral blood risk index-PCMI, distinguishing high and low mortality risk subgroups in the derivation was accurately predictive of mortality in the validation cohort. Song et al. [65] found that the predictive model of survival includes biomarkers (MMP7, SPA, KL6) and clinical variables (FVC%, DLCO%, age, change in FVC at six months) is better than the model based on clinical parameters.
Herazo-Maya et al. [207] have recently identified a 52-gene signature in peripheral blood mononuclear cells of patients with IPF, and y further validated in six different cohorts of patients with IPF. They developed a SAMS (Scoring Algorithm for Molecular Subphenotypes) risk scoring system based on the 52-gene signature. Applying SAMS, low risk and high-risk groups of IPF patients with significant differences in outcome (mortality or transplant-free survival). This 52-gene signature could be valuable in predicting response to therapy.
In testing the idea that a combination of clinical and biological parameters can improve IPF patients’ outcomes prediction, Adegunsoye et al. [208] derived a clinical-molecular risk (CMR) score (CA-125, MMP7, YKL-40, OPN, age, and percent predicted FVC) for treatment exposed patients. They found that a clinical-molecular signature of IPF transplant-free survival may provide a reliable predictor of outcome risk in anti-fibrotic treated patients. This risk score may help identify individuals at risk of poor outcomes despite antifibrotic initiation and open the discussion of the application of CMS risk score before initiation of antifibrotic therapy to identify patients warranting closer clinical monitoring or earlier lung transplant referral [209].
Within the last decade, a broad range of molecular biomarkers for IPF has been reported. Until now, despite a large number of publications about IPF biomarkers, their use in routine is not recommended in international clinical practice yet. The successful translation of molecular biomarkers into clinical practice requires validation in large, multi-center, prospective studies with long-term, longitudinal follow-up, standardization of assays, serial measurements of biomarkers, and interventional trials that show changes related to clinical IPF state.
However, most data about IPF biomarkers originate from small-sized, single-center studies of the retrospective design, cross-sectional with measurements at a single time-point, and often in Asiatic cohorts of patients where their use is more common. This raises questions about the generalizability of the results obtained in Asiatic cohorts as well as about the determination of an optimal cut-off. Their accuracy should also be confirmed in non/Asiatic, Caucasian cohorts to routinely apply them in the management of IPF.
Furthermore, diagnostic criteria for IPF have recently changed, and most of the studies published before did not systematically use HRCT or histology. However, using these stringent criteria, confident data regarding biomarkers value could be obtained. Also, the gold standard for measuring disease activity is missing.
The validation of useful and accurate diagnostic markers could reduce uncertainty and the use of the invasive procedure. Inter-assay disagreement can represent a confounding factor in the interpretation of test results in different studies, and the definition of an optimal cut-off is very important.
Finally, as already touched on in the chapter, investigators are resorting to panels of multiple biomarkers to differentiate IPF patients more effectively from healthy volunteers or patients with other pulmonary diseases. The use of a biomarker index composed of multiple biomarkers already studied separately, with the aim of improving diagnostic accuracy in distinguishing IPF from other ILDs or healthy controls, is promising.
There is evidence of extremely strong genetic association in IPF. Recent advances in genetic sequencing and bioinformatics have made it much easier to detect genetic variants rapidly. It seems that in the near future, we will be able to analyze genetic markers to gain prognostic information for IPF patients or help screen at-risk patients with a familial history that do not exhibit signs or symptoms of IPF.
The utilization of high-throughput sequencing to detect microbial and/or viral genetic material in bronchoalveolar lavage fluid or lung tissue samples has amplified the ability to identify and quantify specific microbial and viral populations [210].
Use of liquid biopsy, which allows the isolation of circulating cell-free DNA from blood, could be very important in the discrimination of patients affected by IPF from those with other ILDs [211].
Discovery, validation, and implementation of clinically useful molecular biomarkers discovered through omics (genomics, epigenomics, transcriptomics, proteomics, and metabolomics) will facilitate precision medicine in IPF [212, 213, 214].
Soon, we expect the results of many clinical trials evaluating as primary or secondary outcomes known and new biomarkers that will convince clinicians of the value of using biomarkers at multiple stages of the diagnosis and personalized management of IPF.
The authors declare no conflict of interest.
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Thus, we discuss how the relations established with the leadership in the work environment can influence the professional development of the subordinates besides the type of learning provided to the workers. This discussion can shift the focus of research—currently centered on learning modes—to a focus on leadership practices for skills development and the consequent career progression of subordinates.",book:{id:"6781",slug:"leadership",title:"Leadership",fullTitle:"Leadership"},signatures:"Luciana Mourão",authors:[{id:"239876",title:"Ph.D.",name:"Luciana",middleName:null,surname:"Mourão",slug:"luciana-mourao",fullName:"Luciana Mourão"}]}],mostDownloadedChaptersLast30Days:[{id:"70045",title:"Islamic Leadership: Comparisons and Qualities",slug:"islamic-leadership-comparisons-and-qualities",totalDownloads:2958,totalCrossrefCites:5,totalDimensionsCites:6,abstract:"This chapter explores the concept and principles Islamic leadership which generate qualities. 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It originates from the concept of reflection defining leadership roles and responsibilities in all types of organizations. Focusing on reflection for learning in an effort to create reflective learning communities for all stakeholders taking part in both administrative and executive positions in organizations, this chapter is expected to contribute to leadership theories, to link theory and practice in concrete terms describing new leadership roles and responsibilities under the reflective thought considering its unique impact on organizational functioning.",book:{id:"5457",slug:"contemporary-leadership-challenges",title:"Contemporary Leadership Challenges",fullTitle:"Contemporary Leadership Challenges"},signatures:"Süleyman Davut Göker and Kıvanç Bozkuş",authors:[{id:"190035",title:"Associate Prof.",name:"Süleyman Davut",middleName:null,surname:"Göker",slug:"suleyman-davut-goker",fullName:"Süleyman Davut Göker"},{id:"190044",title:"Dr.",name:"Kivanc",middleName:null,surname:"Bozkus",slug:"kivanc-bozkus",fullName:"Kivanc Bozkus"}]},{id:"52779",title:"Leadership and Gender Differences—Are Men and Women Leading in the Same Way?",slug:"leadership-and-gender-differences-are-men-and-women-leading-in-the-same-way-",totalDownloads:5540,totalCrossrefCites:7,totalDimensionsCites:8,abstract:"In this chapter, we aim to highlight the main gender differences in terms of leadership, to provide a critical comparative analysis, to discuss potential barriers that need to be overcome, and to find some ways of increasing organizational performance through a better leadership style. The focus will not be placed on the gender differences by themselves but on the ways these differences can positively influence the organizational performance. Our proposed chapter is mainly based on literature review as a methodology in its own right. Since literature review has revealed quite many divergent opinions, we also used questionnaires and interviews as data collection tools and we intend to present some of our results, without aiming to generalize all these results to different cultures. We cannot conclude that men’s leadership skills are more powerful and more important than women’s skills or vice versa, but it is clear that gender differences do exist and people should capitalize on them. 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Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,annualVolume:11410,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). 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