More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
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Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
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“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
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Additionally, each book published by IntechOpen contains original content and research findings.
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We are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\n
Simba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
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IntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\n
Since the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\n
Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n
“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\n
Additionally, each book published by IntechOpen contains original content and research findings.
\n\n
We are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n
\n\n
\n'}],latestNews:[{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"},{slug:"intechopen-s-chapter-awarded-the-guenther-von-pannewitz-preis-2020-20200715",title:"IntechOpen's Chapter Awarded the Günther-von-Pannewitz-Preis 2020"},{slug:"suf-and-intechopen-announce-collaboration-20200331",title:"SUF and IntechOpen Announce Collaboration"}]},book:{item:{type:"book",id:"5058",leadTitle:null,fullTitle:"Organic Farming - A Promising Way of Food Production",title:"Organic Farming",subtitle:"A Promising Way of Food Production",reviewType:"peer-reviewed",abstract:"Organic farming is a progressive method of farming and food production it does not mean going back to traditional (old) methods of farming. Many of the traditional farming methods used in the past are still useful today. Organic farming takes the best of these and combines them with modern scientific knowledge. Authors' task was to write a book where many different existing studies could be presented in a single volume, making it easy for the reader to compare methods, results and conclusions. As a result, studies from different countries have been compiled into one book. I believe that the opportunity to compare results and conclusions from different authors will create a new perspective in organic farming and food production. 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\n
1. Introduction
\n
Matrix metalloproteinases (MMPs) represent group of 25 endoproteases, which require a presence of zinc ions to reveal their proteolytic activity. According to worldwide accepted nomenclature, MMPs have assigned numbers from 1 to 28. However, till now no respective molecules have been ascribed for numbers 4, 5 and 6, whereas MMP-18 was identified only in Xenopus frogs. [1, 2] Apart from regulation of extracellular matrix (ECM) turnover, MMPs are also involved in controlling of numerous non-ECM molecules, including cytokines and growth factors. Thus, MMPs are key molecules in embryo- and organogenesis, angiogenesis and tissue regeneration. However, they are also main destructive factors, responsible for cancer progression, aortic aneurysm rupture or delayed healing of chronic wounds. [3, 4] Recently, their involvement was postulated also in some inflammatory diseases affecting respiratory tract, among them chronic obstructive pulmonary disease and asthma. [5] In this chapter authors will focus especially on possible role of MMPs in asthma and asthma-associated alterations in architecture and function of respiratory tract mucosa, which are better known as airway remodeling.
\n
\n
\n
2. MMPs — portrait of the family
\n
\n
2.1. MMP structure
\n
Based on molecular structure, substrate specificity and mechanism of activation, MMPs are classified into four groups: gelatinases, matrilysins, archetypal MMPs and furin-activated MMPs (Fig. 1.). Formerly, MMPs were divided into six types – collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs and others. However, nowadays this classification possesses rather historical meaning. The overall structure of MMPs reveals some common features, which are similar in all members of the family. [2, 3] One of these features is the presence of signaling peptide, located on the N-terminus of newly synthesized proteins. This leader sequence is necessary for the insertion of maturating MMP molecule into cistern of endoplasmic reticulum, and then it is removed. Unlike to other family members, in MMP-23 the N-terminal signaling sequence is substituted by a type II transmembrane domain, which allows anchorage of these molecules in cell membrane.
\n\n
The next part common in MMP structure is approximately 80 amino acid-long prodomain. It contains conserved “cysteine switch” motif, responsible for maintaining the latent form of enzyme by the blockade of its catalytic site. The main constant segment present in all family members is their catalytic domain. This sphere-like domain is composed of 160-170 amino acids. It contains shallow slot with two zinc ions inside, which constitutes an active site of MMP molecule. Exclusively, catalytic domains in both gelatinases, MMP-2 and -9, contain unique fibronectin II-like inserts. Most MMPs (except for MMP-7, -23 and -26) have short hinge segment of approximately 10-30 amino acids, which connects the catalytic domain with hemopexin-like domain. Exceptionally, MMP-9 molecule has the longest hinge region, composed of 64 strongly O-glycosylated amino acids. The C-terminal hemopexin-like domain, not present in MMP-7, -23 and -26, is composed of approximately 200 amino acids and is considered as docking spot for tissue inhibitors of MMPs (TIMPs). In MMP-23 molecule the hemopexin-like domain was replaced by a cysteine-rich immunoglobulin-like domain.
\n
The representatives of membrane-type (MT) subgroup of MMPs (except of already mentioned MMP-23) have hemopexin-like domain connected to a type I transmembrane domain with a short intracellular tail (MMP-14, -15, -16 and -24, also known as MT1, -2, -3 and -5-MMP, respectively), or a cell membrane-anchoring glycosylphosphatidylinositol (GPI) moiety (MMP-17 and -25, known as MT4- and MT6-MMP) (Fig. 1).
\n
Fig. 1.
Schematic representation of MMPs family. (A). Main groups of the family and their structure. (B). An example of schematic structure of MMP. Detailed description in text.
\n
Finally, three of secreted MMPs (MMP-11, -21 and -28), all the membrane-type MMPs and MMP-23 have a specific sequence between their prodomain and the catalytic domain, which is recognized by furin. This subtilisin-like serine proteinase from trans-Golgi apparatus and the endoplasmic reticulum removes the prodomain from the catalytic domain and thus may lead to intracellular activation of MMP molecule. [1–6]
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2.2. Substrate specificity
\n
MMPs are able to digest main components of extracellular matrix (ECM), including high molecular weight polymers of native and denatured collagens and elastin, as well as small ECM molecules, like fibronectin, laminin and aggrecan. Moreover, MMPs may process numerous non-ECM molecules, among them various adhesion molecules, dystroglycan, syndecans, growth factors, pro-cytokines, and their receptors. MMPs were shown to activate via proteolysis pro-forms of interleukin (IL)-1β, IL-8, tumor necrosis factor (TNF), Fas ligand, transforming growth factor (TGF)-β, but also other members of MMPs family (Table 1). [1, 3, 7–9] Noteworthy, some of these cytokines, including vascular endothelial growth factor (VEGF) and TGF-β, may be further entrapped in three-dimensional net of extracellular matrix components or by their binding proteins. Therefore, MMPs may be necessary to reveal biological activity of these factors, through their enzymatic discharge from ECM.
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\n
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\n
\n\n
\n
Group
\n
Representatives
\n
Main ECM substrates
\n
Non-ECM substrates
\n
\n\n\n
\n
\nARCHETYPAL MMPs\n
\n
\nCollagenases\n MMP-1, -8- 13
\n
collagens, gelatin, fibronectin, aggrecan…
\n
pro-IL-1β, pro-IL-8, pro-TNF, other MMPs, PAI, IGFBM
pro-IL-1β, other MMPs, IGFBP, MMP/TIMP complex, fibrinogen, plasminogen, antitrombin III
\n
\n
\n
\n
Others\n MMP-12, -19, -20, -27
\n
collagen IV, gelatin, elastin, fibronectin, laminin
\n
fibrin, plasminogen, myelin basic protein
\n
\n
\n
\nMATRILYSINS\n MMP-7, -26
\n
collagen IV, gelatin, elastin, fibronectin, laminin, integrins…
\n
other MMPs, MMP/TIMP complex, fibrinogen, plasminogen
\n
\n
\n
GELATINASES\n MMP-2, -9
\n
collagens, gelatin, elastin, fibronectin…
\n
pro-IL-1β, plasminogen, other MMPs
\n
\n
\n
\nFURIN-ACTIVATED MMPs\n
\n
\nSecreted\n MMP-11,-21,-28
\n
collagen IV, gelatin, laminin, fibronectin
\n
casein, IGFBP
\n
\n
\n
\nType 1 transmembrane\n MMP-14,-15,-16,-24
\n
collagens, gelatin, elastin, laminin, vitronectin
\n
other MMPs
\n
\n
\n
\nGPI-anchored\n MMP-17,-25
\n
UNK
\n
\n
\n
\n
\n
Type II transmembrane MMP-23A,-23B
\n
UNK
\n
\n
\n\n
Table. 1.
Representatives of MMPs family with their main substrates (detailed description in text). ECM – extracellular matrix, Non-ECM- other substrates, PAI – plasminogen activator inhibitor, IGFBP – insulin-like growth factor-binding protein, TIMP – tissue inhibitor of MMPs, UNK – unknown.
\n
\n
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2.3. MMP expression
\n
Due to a high proteolytic activity and broad substrate specificity, MMPs are recognized as key molecules, engaged in cell proliferation and migration, tissue growth, remodeling, and regeneration. For this reason their expression and activation has to be maintained under precise multistage control. These controlling mechanisms include regulation of gene expression, post-transcriptional and post-translational modifications, but also several ways of pro-enzyme activation or inhibition of active MMP. [3, 4] Nevertheless, if these mechanisms fail, similarly to the well known character from the famous novella by R.L. Stevenson, “Strange Case of Dr. Jekyll and Mr. Hyde”, MMPs may also reveal their dual nature. Without sufficient supervision, these endoproteases may become highly dangerous effector molecules, engaged in various pathologies. These conditions include cancer metastasis, formation and rupture of aortic aneurysm, delayed healing of chronic wounds and many others. [1, 3, 10, 11] Recent studies have provided evidence that MMPs may also be involved in pathogenesis of asthma, mainly asthma-associated airway remodeling. [5]
\n
Among all MMPs, only MMP-2 and MMP-9 are produced constitutively, whereas the expression of majority of MMP genes requires some trigger, e.g. tissue damage, or inflammatory reaction. It was found that the promoter region of genes encoding for MMPs comprises sequences recognized by two main specific transcription factors, AP-1 and NF-κB. Both transcription factors merge expression of many inflammatory response-engaged molecules, including MMPs with several intracellular signaling pathways, induced by cytokines and growth factors. Indeed, it was proved that MMPs expression may be controlled by variety of growth factors, including TGF-β, platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and pro-inflammatory cytokines (e.g. IL-1β, IL-6, TNF, etc.). Moreover, the promoter activity of MMPs may also be supervised by family of Ets transcription factors. Since their conserved binding site is located close to target sequence for AP-1, they may interact each other and thus modulate promoter response to various stimuli. [3, 4, 10, 12–14]
\n
The rigid control of MMP genes expression may also be granted by their epigenetic modification. This mechanism is based on alteration in chromatin conformation, which is mediated by differential acetylation-deacetylation of nucleosomal units, due to activity of an enzyme – histone deacetylase (HDAC). Noteworthy, it has been shown that such regulation may result in various responses of particular MMP genes. In vitro stimulation with TNF or IL-1β, with simultaneous suppression of HDAC activity resulted in decreased expression of MMP-1 and MMP-9, but increased production of MMP-3. [14, 15] Finally, the expression of MMPs may also be modified on the post-transcriptional level, by the influence on stability or degradation of their transcripts. Recently, it has been proven that the expression of several MMPs may be negatively regulated by the small molecules of non-coding RNA, known as microRNAs (miRs), in mechanism of RNA interference. It has been demonstrated that miR-9, miR-24 and miR-133a may bind to the 3’-UTR of mRNA for MMP-14 (MT1-MMP) and they directly block its translation. On the other hand, down-regulation of miR-199a-5p in murine model induced MMP-1, possibly via Ets-1 derepression. [16–19]
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2.4. MMP activity
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All members of MMPs family are expressed as inactive pro-enzymes. This condition is assured by previously mentioned “cysteine switch”, a specific interaction between zinc cations from the active site of the catalytic domain, and a cysteine thiol group from the prodomain. The renouncement of inhibitory influence of the prodomain on the catalytic domain is critical for activation of pro-enzyme and may take place in two concurrent ways (Fig. 2). [3, 14, 20]
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Fig. 2.
MMPs activation. (A) Two pathways of MMPs activation. (B) Schematic representation of substrate cleavage. Detailed description in text.
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2.4.1. Activation
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The first pathway of MMPs activation is based on direct cleavage of their prodomain. It may be carried by several extracellular proteolytic enzymes, including other MMPs, as well as cysteine, serine and aspartate proteases. This pathway also involves already mentioned intracellular processing and activation by furin. Due to removal of prodomain, molecular weight of pro-enzyme activated in this pathway is significantly reduced, as compared to its initial size. Thus, in zymograms of substrate-specific zymography with SDS-polyacrylamide gel electrophoresis (PAGE) the activated MMP appears as the lower band, below that, corresponding to latent form of enzyme. [21–23]
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The second pathway depends on interaction of cysteine thiol groups from prodomain with various compounds, including free radical, disulfides, some detergents with sodium dodecyl sulphate (SDS), alkylating agents, heavy metal ions and organomercurials, with 4-aminophenylmercuric acetate (APMA). This interaction may induce allosteric conversion in MMP structure, which leads to an exposure of the active site in the catalytic domain. Therefore, although the prodomain still remains attached to the entire molecule, such MMP may reveal its proteolytic activity. On the other hand, that MMP, despite being activated, has the same molecular weight, as its inactive pro-form. That explains, why such full length-MMP may be visualized in zymograms on the same level as latent pro-MMP. Noteworthy, the prodomain may be further removed by auto-cleavage, that results in decrease of MMP molecular size and, similarly to the first pathway, an appearance of the lower band in zymograms. [3]
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Results of recent studies suggest that in vitro proteolysis requires only a substrate and respective MMP, whereas in vivo systems usually involve some additional component. These accessory factors may include membrane-, or ECM-associated peptides and glycosaminoglycans, which may determine specificity, as possibly, catalytic rate of MMPs. Accordingly, such accessory molecules may work as a kind of adapters, which bind a substrate and MMP and thus enable their close interaction with an effective concentration. [21–23]
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2.4.2. Inhibition
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As was already noticed, the precise control of MMPs expression and activity is essential for homeostasis of the entire body. Therefore, to counterbalance the mentioned stimulators and activators of MMPs, some agents revealing inhibitory properties are also required. Apart from best known family of specific tissue inhibitors of metalloproteinases (TIMPs), there are also less specific endogenous inhibitors, among them α2-macroglobulin, family of serine proteinase inhibitors (serpins), thrombospondin-1 (TSP-1), tissue factor-pathway inhibitor (TFPI)-2, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), etc. [3, 10, 21, 24]
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Members of TIMPs family (numbered from 1 to 4) are the best identified specific endogenous inhibitors of MMPs. They are expressed and released by various cell populations, including macrophages, platelets, smooth muscle cells, etc. The mechanism of their action depends on reversible chelating of Zn2+ cations from active center of MMP’s catalytic domain and, thus, abolishes its proteolytic properties. Since MMP – TIMP interaction occurs in a stoichiometric ratio 1:1, the MMP/TIMP ratio seems to better reflect presumable biological impact of both agents, instead of absolute amount of each of both proteins. Moreover, it is noteworthy that studies concerning in vivo interactions between MMPs and TIMPs are also interfered by the highly effective serum antiprotease – α2-macroglobulin. [3, 6, 14]
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Although all TIMPs may interact with various MMPs, they differ in their specificity, e.g. TIMP-1 preferentially binds to membrane type-MMPs, whereas TIMP-2 is considered as important regulator of MMP-2 activity. Interestingly, the latter regulation actually involves TIMP-2-dependent activation of MMP-2. In this unique mechanism TIMP-2 works as bridging molecule between hemopexin domain of MMP-2 and MT1-MMP (MMP-14), which mediates cleavage of prodomain in “immobilized” MMP-2.
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Apart from mentioned above endogenous MMPs inhibitors, there is also an increasing number of exogenous compounds, which reveal direct and/or indirect modulatory properties towards the activity of MMPs. [3, 4] Since they have potential clinical relevance in a treatment of asthma and asthma-associated remodeling, they will be further described in next paragraph (see 2.7).
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2.5. Methods of MMP measurement
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Increasing interest in the role of MMPs in asthma and, especially, asthma-associated remodeling encouraged scientists to develop more specific and sensitive methods to detect MMPs in analyzed samples. However, main obstacle in MMPs research is that most commonly used methods, i.e. enzyme-linked immunosorbent assay (ELISA) and zymography, do not allow simultaneous assessment of amount and activity of MMPs. [3]
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2.5.1. ELISA
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Standard ELISA is a routine laboratory technique, which allows a quantitative detection of minute amounts of MMPs in solution (picograms per ml) using specific antibodies, usually conjugated with peroxidase-based detection system. Noteworthy, standard method provides data concerning specific protein concentration, without any information regarding actual activity of MMPs. Nevertheelss, such activity could be roughly estimated using specially designed ELISA sets, which enable differentiation between truncated forms of activated MMPs and prodomain-containing latent MMPs. However, as mentioned above, allosteric activation not necessarily leads to prodomain removal. Therefore, data provided by ELISA alone are not fully conclusive, and should be verified by some activity assay. [3]
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2.5.2. Zymography
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The substrate-specific zymography is the most commonly used method to evaluate MMPs activity in tested samples. This assay is based on initial separation of samples using electrophoresis in modified polyacrylamide gel, followed by its incubation in reaction buffer and subsequent staining. The key component of such modified gel is substrate, specific for enzyme being analyzed (e.g. collagen for MMP-1 and -13, gelatin for MMP-2 and -9, casein for MMP-1, -3, -7, -10, -12, -13), which is homogenously distributed in whole gel volume. Since polyacrylamide gel contains sodium dodecyl sulphate (SDS), the speed of migration in electrophoresis is determined by molecular weight of separated proteins, resulting in shifted local condensation of full length pro-enzyme and truncated forms of MMPs. During incubation in calcium- and zinc-rich reaction buffer, MMP molecules become reactivated and digest own specific substrate only in place of their condensation. After wash in the staining solution, e.g. Coomassie Brilliant Blue, the entire gel becomes stained, with except of unstained area corresponding to digested substrate. Noteworthy, when compared to respective molecular weight standard, the localization of unstained area enables better identification of analyzed MMP, whereas the size of digested / unstained bands well correlates with amounts of detected enzyme. This amounts may be further determined by comparison to reference sample, e.g. known amounts of recombinant MMP. [3, 25]
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Although substrate-specific zymography is sensitive (picograms per sample), and relatively cheap method, it has some weak points. The first issue is long and time-consuming protocol. The next, more important concern, is uncontrolled allosteric activation of MMP mediated by SDS. Since it may strongly affect results of assessment, in current research standard zymography is often replaced by other, faster and more reliable activity assays.
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2.5.3. Fluorescent activity assay
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The unintended interaction with SDS may be avoided, when instead of polyacrylamide gel, MMPs activity is assessed in SDS-free reaction mixture. The measurement of substrate proteolysis in solution implements technology of fluorescence resonance energy transfer (FRET) using substrate (e.g. casein or gelatin) tagged with fluorochrome and quencher. Until labeled substrate stays untouched, the entire energy from fluorochrome is absorbed by quencher, with no fluorescence detectable. When the substrate is cleaved, the fluorochrome-quencher interaction becomes disrupted, that is associated with increased emission of fluorescence under UV light. Since the increase of fluorescence is proportional to enzyme activity, with known quantities of MMP as reference, and with fluorescence reader, this method allows very fast (within few minutes) measurement of proteolytic activity revealed by small amounts (nanograms per ml) of MMP in tested samples. [3, 26]
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Noteworthy, in contrast to standard zymography, the fluorescence assay enables studies on proteolytic activity of MMPs, and analysis of modulation of this activity by various agents, e.g. natural and synthetic inhibitors. However, the method is very sensitive to reaction conditions, which may vary depending on protocol of sample preparation. The key factors are concentration of non-ionic detergents, and presence of exogenous protease inhibitors (frequently used to prevent proteolysis in biological material) or metal ion chelators (e.g. EDTA). On the other hand, the tissue sample preparation itself may lead to artificial activation of MMPs or release of their natural inhibitors. [3]
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The main disadvantage of the basic variant of mentioned fluorescent method is its non-specificity. Therefore, when analyzing biological samples, to determine, which MMP contributes to the degradation of labeled substrate, it is necessary to use a panel of MMP-specific antibodies, to inhibit proteolytic activity of selected enzyme. Although a such approach enables precise identification of all contributors of observed proteolytic activity, it also significantly increases the cost of that analysis.
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2.5.4. Immunozymography assay
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Recently, a modification of mentioned above fluorescent method was introduced into market. The method combines specificity of standard ELISA and functionality of fluorescent activity assay. In a first step the sample is applied onto test plate, coated by antibody specific for MMP of interest. Then MMP molecules, which are captured by antibody, convert a latent detection reagent into its active form. The activated detection reagent catalyzes enzymatic conversion of colorless substrate into color product. Since the amount of product directly correlates with number of active MMPs, the use of standard calibration curve allows precise measurement of active MMP molecules concentration in tested samples. Furthermore, when using organomercurials (e.g. APMA) to activate pro-MMPs in tested material, it also allows an assessment of latent form of MMPs. Thus, the assay incorporates advantages of standard zymography (the assessment of MMP activity and discrimination between pro- and active forms of these enzymes), specificity of ELISA and exceptional sensitivity, reaching 0.1 pg/ml. Therefore, it may be the best choice for research concerning MMPs activity in samples, where the minute amounts of MMPs are expected, e.g. condensates of exhaled air. [27]
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2.5.5. In situ zymography
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The distribution of MMPs in tissue specimens may be studied using immunohistochemistry. However, to assess the local activity of these enzymes, directly on the place of their production, the in situ zymography may be used. Similarly to mentioned above fluorescent activity assay, this method also utilizes FRET technology. The tested specimen is incubated with substrate labeled with fluorochrome-quencher complex and then analyzed using fluorescent microscope, or confocal laser scanning microscope. Similarly to fluorescent activity assay, in situ zymography does not identify particular MMPs, unless used with specific neutralizing antibodies. Furthermore, it does not provide information concerning quantities of active MMP. Nevertheless, it is still valuable supplement to other methods in MMPs research. [3]
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2.5.6. Reverse zymography
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As previously mentioned, various factors which affect MMPs activity, may be analyzed using fluorescent activity assay, western blot or respective ELISA. However, to detect natural tissue inhibitors of MMP (TIMPs) some functional assay, better known as reverse zymography, has been developed. The method is based on specific interaction between TIMPs from analyzed sample and MMP of interest. Similarly to standard zymography, samples are separated in polyacrylamide gel, which is supplemented with homogenously distributed substrate (e.g. gelatin), but also selected MMP. After electrophoresis the gel is incubated in reaction buffer. Since both, MMP and substrate, are present in the entire gel volume, MMP cleaves the whole substrate, except of places corresponding to the TIMPs condensation after electrophoresis. In these places TIMPs protect substrate from digestion, therefore, after Coomassie staining they appear as blue bands, whereas the remaining gel volume stays unstained. [3]
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2.6. MMPs in patients with asthma
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2.6.1. Mr. Hyde…?
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Extensive studies, focused on asthma and asthma-associated airway remodeling, have revealed clear involvement of MMPs in pathogenesis of that disease. [5] However, the exact role of MMPs in this process remains vague. The postulated link between metalloproteinases and asthma was based mainly on observations concerning increased amounts and/or activities of various MMPs in samples collected in patients with asthma. The samples were obtained using various methods of collection and/or various material, among them serum or plasma, mucosal biopsies, induced sputum, broncho-alveolar lavage (BAL) fluid and, most recently, exhaled breath condensates (EBC). [27–31] Majority of studies concerned MMP-9, however, other MMPs, including MMP-1, -2, -3, or -12 were also studied. It is noteworthy that substrate specificity of mentioned MMPs entirely enables their self-sufficient work with full repertoire of ECM components. Collagen IV, and laminin, two main components of basement membranes, are cleaved by MMP-9 and MMP-12. Native molecules of collagen I, main fibrillar ECM component of mucosal connective tissue, are initially digested by MMP-1, whereas their further degradation may be continued by all mentioned MMPs (MMP-2, -3, -9, and -12). Elastin molecules are degraded mainly by MMP-12, but also MMP-2 and -9. [3] Although nominal values of MMPs (especially MMP-9) concentrations differed between various studies, in vast majority of mentioned reports similar regularity was observed. MMPs levels and /or activity in individuals with asthma were several fold higher than in control subjects. [28, 29, 32] The number of MMPs-positive cells in sputum or BAL inversely correlated with values of forced expiratory volume in 1 second (FEV1), whereas MMPs amounts in sputum, BAL and EBC positively correlated with severity of disease. They were significantly higher in severe asthma or in asthma exacerbation, and lower in mild asthma or in remission. [31, 33] Also bronchial smooth myocytes/myofibroblasts (BSM) from mucosal biopsies of patients with fatal asthma produced increased levels of MMP-9 and -12, whereas BSM from non-asthmatics expressed only small quantities of MMP-2,-3 and -9. [34]
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These observations could support concept of “destructive hypothesis”, which emphasizes detrimental effect of metalloproteinases on disease progression. In this scenario, similarly to Mr. Hyde from previously mentioned novella by R.L. Stevenson, MMPs reveal their dark nature. The overexpression and hyperactivation of these enzymes may result in progressive damage of epithelium, basement membrane and subepithelial connective tissue. These events may endorse local inflammatory reaction, and thus further increase the damage zone. [5, 35] On the other hand, they may induce excessive and poorly controlled tissue repair, with increased deposition of ECM components, proliferation and hypertrophy of myofibroblasts, as well as goblet cells hyperplasia with mucus hypersecretion. These changes result in structural and functional changes in bronchial tree mucosa, which is known as airway remodeling (Fig. 3). [5, 34] In fact, in animal model of asthma it was found that an increase in MMP-9 activity in the airway mucosa was associated with epithelial damage, alteration of subepithelial basement membrane, but also increased levels of TGF-β and subepithelial collagen deposition. [36, 37] In patients with asthma Vignola and coauthors have observed positive correlation between sputum levels of MMP-9 and the intensity of functional and structural abnormalities, which may be easily visualized using air flow measurement and high resolution computed tomography, respectively. [38, 39]
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Fig. 3.
Schematic representation of the “destructive hypothesis”. Detailed description in text.
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Interestingly, some authors did not confirm direct correlation of MMPs levels with symptoms severity, especially when using serum or plasma samples for the analysis. [30] The last finding may suggest that a main source of MMPs overproduction in asthma is located in airway system, with limited systemic influence. This assumption may be supported by association between MMP-9 level measured in breath condensates and predominant population of inflammatory cells in induced sputum or BAL. Barbaro and coauthors have shown that patients with neutrophilic airway inflammation revealed MMP-9 concentrations significantly higher than individuals with severe eosinophilic asthma. [40] Thus, one could conclude that, essentially, neutrophils and, to a lesser extent, eosinophils would be main sources of MMPs in mild and severe asthma. Nevertheless, there is strong evidence that functional and structural changes in bronchial wall are also contributed by other producers of MMPs – epithelial cells, bronchial smooth myocytes, fibroblasts and mast cells. [5, 27] In fact, recent studies have shown that epithelium- and myocytes-derived metalloproteinases may be involved in pathogenesis of asthma and asthma-associated remodeling much earlier, even before clinical manifestation of first symptoms. That hypothesis emerged as an ancillary result of embryological studies, focused on development of bronchial tree. It has been proposed that pouches of epithelium, submerged in mesenchyma, work together during organogenesis as an functional entity, which was named the epithelial-mesenchymal trophic unit (EMTU). [41] Apart from large variety of cytokines and growth factors, produced by EMTU during embryogenesis, the important role in regulation of bronchial growth play metalloproteinases. Their list is still expanding and includes several soluble MMPs, mainly MMP-3, -9 and -12 [34, 42], as well as membrane-type 1 MMP (MT1-MMP/MMP-14). [43] The latter is involved in regulation of cell proliferation, migration and differentiation, since all these events are in some extent associated with pericellular proteolytic activity of this membrane-bound MMP.
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Recently, another membrane-bound metallopeptidase, member of distinct class of disintegrin and metalloproteinases (ADAM), denoted as ADAM33, has been added to this list. [44] Similarly to MT-MMPs, function of these metalloproteinases relies on degradation of ECM components located in the close proximity to the cell, that enables further growth and branching of respiratory tree. However, this involvement also comprises processing of cytokines and their receptors. Therefore, although they remain under strict control, including methylation-dependent epigenetic regulation of promoter activity [45], even small abnormality in that system may be responsible for aberrant function of EMTU. This may lead to enhanced response to some stimuli, e.g. oxidative stress or viral infection. [46] Such triggers may result in reactivation of EMTU in adulthood, excessive stimulation of epithelial cells and bronchial myofibroblasts. They start again to express large quantities of metalloproteinases and cytokines, among them TGF-β. Both mentioned enzymes, ADAM33 and MT1-MMP/MMP-14, are supposed to trigger TGF-β-dependent stimulation of BSM and subepithelial fibroblasts, which, in response, start with excessive production and deposition of ECM components. Hereby EMTU reactivation may be associated with an increased risk of airway malfunction. Interestingly, in some individuals the initial ultrastructural changes in basement membrane, a characteristic feature of asthma-associated remodeling, were observed long before the onset of clinical symptoms of disease. [47, 48] Accordingly, one could expect, that EMTU hypothesis should be supported by some genetic background. Indeed, analysis of genome-wide association has indicated the possible role of nucleotide polymorphisms of metalloproteinases in increased susceptibility to asthma. [49] Among them, a significant association with early onset of bronchial hyperresponsiveness and asthma was noted in case of several polymorphic variants of ADAM33. [50] However, due to ethnic variability, the significance level of this association differs between analyzed populations. Noteworthy, among analyzed polymorphisms of ADAM33, only T1, V4, T+1 and F+1 variants were found to correlate with asthma in the general population [51], whereas other, including ST+7 or haplotype H4, were characteristic solely for certain populations. [52, 53]
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Furthermore, several groups have suggested correlation between increased risk of asthma development and occurrence of some nucleotide polymorphisms in genes encoding for “classic” matrix metalloproteinases, mainly MMP-9. The postulated associations concerned single nucleotide polymorphisms (SNPs) of MMP-9 gene, located in promoter region (-1562C/T), the substrate binding site in catalytic domain (279Q/R) and TIMP docking region of hemopexin domain (574P/R and 668R/Q). [5, 54] However, majority of mentioned studies were conducted in rather small groups, with various ethnic origins. Therefore, results of these studies, although relevant, should be considered with some caution. Till now, based on studies involving group of 4,000 children, only allele R of 279 SNP was confirmed as being associated with significant increase of asthma risk. [54] On the other hand, some SNPs in MMP genes may also be associated with eventual benefit for a patient. Recently, the mutant T allele of MMP-2 promoter (-1306C/T) SNP, supposed to decrease MMP-2 production, has been described as conferring significant protection against asthma in North Indian population. [55]
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2.6.2. … or Dr. Jekyll ?
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As already mentioned, research involving asthma patients, animal models and in vitro studies provide strong support for “destructive hypothesis”. [56] MMPs are abundantly produced and activated during acute and chronic asthma, and their level negatively correlates with lung function. However, those observations should be interpreted with some caution, especially since recent studies yielded some contradicting data. [57, 58] Based on these data an opposite, or “protective hypothesis” has been formulated. According to this concept, MMPs are responsible for cleavage of excessive amounts of ECM components, which are secreted in response to inflammation-mediated damage of mucosa. [59] Therefore, MMPs are supposed to protect mucosa from uncontrolled fibrosis, whereas their natural inhibitors – TIMPs (especially TIMP-1), since they prevent cleavage of abnormal ECM deposits, would, paradoxically, appear as key detrimental molecules in that system (Fig. 4). In fact, increased TIMP-1 concentrations in BAL were related to persistent wheezing in preschool children. [31] However, an attribution of altered ECM turnover solely to MMPs activity or TIMPs concentration seems to be unfounded simplification. Presumably, enhanced accumulation of matrix components results rather from imbalance between proteolytic activity of MMPs and anti-proteolytic properties of TIMPs. Consequently, instead of absolute levels of MMPs or TIMPs, their relative amounts, expressed as respective MMP/TIMP ratios, may be more relevant for course of disease. Indeed, in several studies decreased MMP-9/TIMP-1 ratio was observed in sputum, BAL and mucosal biopsies of adults and children with asthma. [60, 61] Moreover, it was associated with the airflow aggravation and reduced airway lumen, observed in computed tomography of asthmatic patients. [62] The low MMP-9/TIMP-1 ratio was also reported in asthmatic smokers with persisted airflow obstruction and thickening of bronchial mucosa. [63]
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Fig. 4.
Schematic representation of the “protective hypothesis”. Detailed description in text.
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When considering protective role of MMPs in asthma and asthma-associated remodeling, their main function concerns normalization of ECM turnover. However, one has to mention MMP-mediated regulation of cell-to-cell and cell-to-ECM interactions, as well as their involvement in cytokines/growth factors network. [56] As previously described, MMPs have been shown to process some cytokines, including TGF-β and VEGF, but also cleave several cell surface receptors, among them fibroblast growth factor (FGF) receptor 1 (FGFR1), CD44, or alpha subunits of receptors for IL-2, -5 and -13. [56, 64–67] Possibly, MMPs could also reveal their protective effect on asthma progression by interference with trafficking of immune cells and/or shedding key receptors engaged in Th2 signaling, thus attenuating allergic inflammation. This hypothesis was confirmed in murine models with MMP-deficient animals. Indeed, in mice lacking MMP-2, -8, -9 or -19 an allergen challenge resulted in increased allergic inflammation and airway hyperresponsiveness with augmented release of Th2 cytokines – IL-4, -5 and -13. [65, 68–74] Interestingly, MMPs deficiency was also associated with delayed clearance of immune cells from the airway. [68, 69, 71] This finding could be explained by involvement of MMPs in conditioning of leukocytes. [71] The possible mechanism of that phenomenon may exploit MMP-9-mediated cleavage of IL-2Rα subunit on the surface of T lymphocytes, which results in down-regulation of their proliferative capacity and subsequent apoptosis. [75] Apart from mentioned Th2 cytokines, MMPs may modulate inflammatory and immune response via processing of CC and CXC chemokines. Metalloproteinases have been shown to cleave macrophage inflammatory protein (MIP)-2 and monocyte chemoattractant proteins (MCPs) – MCP-2, -3, and -4. [76, 77]
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The data mentioned above imply, that allergic inflammation and airway remodeling seem to be intricately related to MMPs activity, since MMPs may represent key mediators, or rather modulators, involved in vigorous crosstalk between airway constituent cells, invading inflammatory cells, and the extracellular matrix. [78] From that point of view the idea concerning protective role of MMPs in asthma and asthma-associated remodeling seems to be convincing. However, the issue becomes more complicated, when analyzing involvement of MMPs in processing of ECM components and their direct input in airway destruction and remodeling. Noteworthy, both concepts, “destructive” and “protective”, may be supported by some clinical data. In fact, there is still reasonable doubt, whether MMPs reveal some similarity to Dr. Jekyll, or they are recognized rather unfriendly, like Mr. Hyde. However, in addition to some philosophical background, this issue has also an outstanding practical meaning, especially in context of possible pharmacological interventions in asthma-associated remodeling, which may be addressed to modulate MMPs activity. Obviously, when favoring “protective” role of MMPs, they would require some support to increase MMP/TIMP ratio. In contrast, if considering the “destructive hypothesis” as more likely, an opposite action should be undertaken. According to that concept, actually the inhibition of MMPs should provide some benefit for patient. Therefore, univocal clarification of that issue is of great clinical relevance.
Apart from previously mentioned (see chapter 2.4.2) endogenous or “physiological” inhibitors, several exogenous MMP modulators are also available. Noteworthy, in addition to few agents originally designed as MMP inhibitors (e.g. batimastat or marimatsat), nowadays in clinical practice are used many drugs, originally not intended to modulate MMPs activity. [3, 4, 10] The list of these agents is still expanding and includes tetracyclines, inhibitors of angiotensin converting enzyme (ACE), inhibitors of cholesterol synthesis (better known as statins), corticosteroids, etc. Some of them display direct inhibitory influence on MMPs activity (tetracyclines, ACE inhibitors), whereas in others mechanism of their action is indirect and more complex. Moreover, modulation of MMPs expression has been related to the use of clarithromycin, imatinib, inhibitors of Rho-kinase, antagonists of VEGF receptors, as well as inhibitors of some signaling pathways, including NF-κB, MAPK, and others (Fig. 5). [79–81]
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Fig. 5.
Schematic representation of main strategies for MMPs modulation. Detailed description in text.
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2.7.1. MMP inhibitors
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The first group of broad-spectrum MMP inhibitors (batimastat, marimastat, ilomastat, etc.) is based on hydroxamate derivatives. These small zinc ion chelators were originally developed as anti-cancer drugs, and were expected to protect from cancer metastasis and tumor-related angiogenesis. [82] In murine asthma model a treatment with these compounds (marimastat, neovastat, GM6001, and others) was associated with reduced development of allergic inflammation, whereas in patients with atopic asthma these agents decreased bronchial hyperresponsiveness after allergen challenge. [68, 83, 84] However, due to low specificity, nearly all first generation synthetic MMP inhibitors may reveal inhibitory activity against various zinc-containing metalloproteins, including numerous non-MMP enzymes and transcription factors. Therefore, due to reported severe adverse effects, including so-called musculo-skeletal syndrome, mentioned compounds are currently withdrawn from the clinical practice. Regrettably, also novel MMP inhibitors, designed to specifically target particular MMPs, although encouraging in animal studies, did not ensure better safety and, most importantly, satisfactory clinical efficacy in humans. [85–90] The possible explanation of unexpectedly low clinical effectiveness of specific MMP inhibitors concerned compensatory induction of other MMPs after specific down-regulation of the target one.
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Noteworthy, some other strategies of MMPs inhibition include use of monoclonal antibodies or anti-sense technologies. [3, 91] However, relatively high cost due to sophisticated technological process, and parenteral route for administration are enumerated as main limitations for development and broad use of these solutions.
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2.7.2. Tetracyclines
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Tetracyclines are natural antibiotics discovered in Streptomyces, which, apart from well defined anti-microbial properties, may also reveal some other, non-antibiotic activities. Tetracyclines may stabilize ECM turnover, presumably by direct inhibition of catalytic site of MMPs, but also indirectly, by suppression of inflammatory cascade and modulation of MMPs expression. [92] Indeed, anti-MMP properties of semi-synthetic tetracycline — doxycycline have been reported in various clinical conditions, including adult periodontitis, abdominal aortic aneurysm, atherosclerosis, autoimmune diseases and in cancer research. [93–96] Thus, doxycycline has received a Food and Drug Administration approval as potent MMP inhibitor, nevertheless its effect on asthma and asthma-associated remodeling still requires extensive studies. Data available from animal studies are promising in terms of attenuated airway hyperresponsiveness after allergen challenge and decreased airway inflammation. [97–99] Moreover, it was observed that long-term administration of doxycycline together with standard therapy was associated with significant improvement in lung function parameters and possible reversal of remodeling in patients with chronic asthma. [100]
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2.7.3. Statins
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The inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, better know as statins, are potent inhibitors of cholesterol biosynthesis. Due to their mechanism of action statins are currently used as standard constituent of primary and secondary prevention of atherosclerosis and arterial insufficiency. In addition to decreasing serum cholesterol levels, statins are know to exert various pleiotropic, cholesterol-independent effects. [3, 101] The latter are mediated by inhibition of isoprenoids, which modulate the function of intracellular signaling molecules. Thus, statins, among them lovastatin, cerivastatin, simvastatin, rosuvastatin, or pitavastatin, may reveal some anti-inflammatory activities, including inhibition of MMPs. Therefore, they have been extensively studied mainly in cancer and cardiovascular diseases. [102, 103] Recently, in a randomized controlled study atorvastatin has been shown to significantly reduce sputum concentrations of acute inflammatory mediators, including MMP-8 and -9, in smoking asthmatic patients. [104] Thus, statins, especially when combined with standard therapy, may offer some protection from exacerbation and, possibly, airway remodeling. Noteworthy, simvastatin was found to modulate TGF-β-induced mesenchymal-epithelial transition of alveolar epithelial cells in vitro. Interestingly, simvastatin sufficiently suppressed TGF-β to induce expression of connective tissue growth factor (CTGF) and MMP-2 and -9, but it failed to reverse TGF-β-induced morphological changes in epithelial cells. [105] Therefore, although that observation could be a rationale behind the use of statins in prevention of subepithelial fibrosis and airway remodeling, this issue still requires further research.
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2.7.4. Renin-Angiotensin System modulators
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Another group of potential MMP modulators comprises several compounds designed to control the function of the renin-angiotensin system (RAS). These agents, although originally designed to manage arterial hypertension through the inhibition of angiotensin-converting enzyme, appeared to be effective also against MMPs. The mechanism of their action is based on dose-dependent, direct blockage of active site in catalytic domain of the enzyme. [3] Interestingly, also antagonists of angiotensin II receptor were found to modulate MMPs expression, possibly by inhibition of NF-κB pathway. [106] Since early clinical experience with modulators of RAS may suggest their great potential in novel therapy of respiratory diseases, these compounds are recently in focus of interest of several groups. [5, 107, 108]
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2.7.5. Inhaled corticosteroids
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Inhaled corticosteroids (ICS) are currently used as a standard treatment to control asthma symptoms. However, it has to be determined, whether they can block or even reverse epithelial–mesenchymal transition and subepithelial fibrosis in the respiratory tract of asthmatic patients. Noteworthy, decreased amounts of MMP-9 in reticular lamina of basement membrane have been recently shown to contribute to the beneficial effect of ICSs on epithelial–mesenchymal transition in chronic obstructive pulmonary disease. [109] Unexpectedly, data from clinical studies in asthmatic patients are limited and disappointing. [27, 110] In particular, no significant decrease in levels and/or activity of MMP-9 was observed after prolonged therapy with ICS in patients with asthma. [27, 111] This finding may suggest that inhaled corticosteroids alone could not be as effective in preventing asthma-associated airway remodeling, as postulated previously. [27, 110]
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In contrast to ICS alone, the improved control of asthma severity, possibly due to better modulation of MMPs system, may be achieved by introducing a combination therapy, which comprises ICS and long acting β-agonists (LABA). Although both, in vitro and in vivo studies, confirmed superiority of combination therapy over ICS or LABA alone in this regard, they did not determine exactly, how this combination may affect MMP levels. [112–114] Possibly, the augmented effect of ICS-LABA combination can be, at least partially, explained by LABA ability to modulate NF-κB signaling pathway. Thus, inhibition of NF-κB will result in decreased expression of MMP-9 gene, as has been recently shown for ultra-LABA – indacaterol. [115] Indeed, combination of ICS with LABA as both, maintenance and reliever therapy, significantly reduced MMP-9 levels in induced sputum of asthmatic patients. [116, 117] Remarkably, MMP-9 levels, observed in patients with asthma before and after combined treatment with ICS and LABA, seem to reflect the intensity of airways remodeling, as they revealed good correlation with bronchial wall thickening, visualized using high-resolution computed tomography. [116]
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2.7.6. Leukotriene-receptor antagonists
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Leukotriene-receptor antagonists (LTRA) may be considered as an alternative to ICS as “first-line asthma-controller therapy” or as “add-on therapy” in patients already receiving ICS. Montelukast, most commonly used LTRA, was found to decrease the expression of MMP-9 in activated eosinophils in vitro. [118] In children with asthma a treatment with LTRA resulted in clinical improvement –reduction of symptoms and increase of peak expiratory flow, which were associated with significant decrease of MMP-9 levels in plasma. [119] In experimental asthma model in mice LTRA treatment was shown to reverse airway remodeling and decreased airway hyperresponsiveness after allergen challenge. Again, mentioned improvement correlated with decrease of MMP-2 and -9 levels in BAL fluid. [120]
\n
\n
\n
\n
\n
3. Conclusions
\n
Despite extensive studies focused on role of MMPs in asthma and asthma-associated remodeling, our knowledge regarding this issue is still far from a satisfactory level. Since there is no agreement among scientists regarding superiority of “destructive” or “protective” concept, the clarification of “Dr. Jekyll or Mr. Hyde ?” issue seems to have outstanding clinical relevance, especially when considering possible pharmacological interventions. Regrettably, the interpretation of results concerning exact place of MMPs in asthma pathogenesis may be impeded by different methodology and various populations analyzed in these studies. Such differences may certainly affect result of MMPs assessment across the studies. [57, 121] On the other hand, these discrepancies can be ascribed to real differences in MMPs amount and/or activity, depending on sample type and disease severity. Furthermore, local expression and activity of individual MMPs may vary in different airway compartments, thus adding complexity to the network of allergic inflammatory response. [61, 78, 122] Accordingly, the distribution of MMP-2, MMP-9 and MMP-12 in bronchial wall was shown to differ between large and small airways. Moreover, it varied between healthy controls and patients with asthma, and further changed depending on severity of disease. [61, 78]
\n
Noteworthy, mentioned compartmental differences may be easily averaged for the entire bronchial tree, especially when using site-unspecific samples, like induced sputum, BAL, breath condensate and, obviously, serum or plasma. On the other hand, due to such averaging, small local changes, although clinically relevant, may be disregarded. Therefore, further research should focus on more precise assessment of distribution and activity of MMPs, the balance between MMPs and their natural inhibitors, as well as association of those findings with alterations in architecture and function of respiratory tract mucosa.
\n
\n\n',keywords:"airway remodeling, asthma, extracellular matrix, matrix metalloproteinase, destructive hypothesis and protective hypothesis",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/49975.pdf",chapterXML:"https://mts.intechopen.com/source/xml/49975.xml",downloadPdfUrl:"/chapter/pdf-download/49975",previewPdfUrl:"/chapter/pdf-preview/49975",totalDownloads:1380,totalViews:442,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:1,dateSubmitted:"September 23rd 2015",dateReviewed:"February 9th 2016",datePrePublished:null,datePublished:"July 6th 2016",dateFinished:null,readingETA:"0",abstract:"Matrix metalloproteinases (MMPs) are Zn2+-dependent endoproteases, which digest extracellular matrix (ECM) components and various non-ECM molecules. Main physiological role of MMPs concerns regulation of tissue remodeling and regeneration. The production and activity of MMPs are tightly supervised by multistage control mechanisms. These mechanisms include regulation of gene expression, and various post-transcriptional/post-translational modifications. However, without proper control MMPs reveal dual nature, similarly to character from the novella by R.L. Stevenson, “Strange Case of Dr Jekyll and Mr Hyde”. They become dangerous molecules, involved in cancer metastasis, or cardiovascular diseases.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/49975",risUrl:"/chapter/ris/49975",book:{slug:"asthma-from-childhood-asthma-to-acos-phenotypes"},signatures:"Katarzyna Grzela, Agnieszka Strzelak, Wioletta Zagórska and\nTomasz Grzela",authors:[{id:"29646",title:"Dr.",name:"Tomasz",middleName:null,surname:"Grzela",fullName:"Tomasz Grzela",slug:"tomasz-grzela",email:"tomekgrzela@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. MMPs — portrait of the family",level:"1"},{id:"sec_2_2",title:"2.1. MMP structure",level:"2"},{id:"sec_3_2",title:"2.2. Substrate specificity",level:"2"},{id:"sec_4_2",title:"2.3. MMP expression",level:"2"},{id:"sec_5_2",title:"2.4. MMP activity",level:"2"},{id:"sec_5_3",title:"2.4.1. Activation",level:"3"},{id:"sec_6_3",title:"2.4.2. Inhibition",level:"3"},{id:"sec_8_2",title:"2.5. Methods of MMP measurement",level:"2"},{id:"sec_8_3",title:"2.5.1. ELISA",level:"3"},{id:"sec_9_3",title:"2.5.2. Zymography",level:"3"},{id:"sec_10_3",title:"2.5.3. Fluorescent activity assay",level:"3"},{id:"sec_11_3",title:"2.5.4. Immunozymography assay",level:"3"},{id:"sec_12_3",title:"2.5.5. In situ zymography",level:"3"},{id:"sec_13_3",title:"2.5.6. Reverse zymography",level:"3"},{id:"sec_15_2",title:"2.6. MMPs in patients with asthma",level:"2"},{id:"sec_15_3",title:"2.6.1. Mr. Hyde…?",level:"3"},{id:"sec_16_3",title:"2.6.2. … or Dr. Jekyll ?",level:"3"},{id:"sec_18_2",title:"2.7. MMP modulation — pharmacological interventions",level:"2"},{id:"sec_18_3",title:"2.7.1. MMP inhibitors",level:"3"},{id:"sec_19_3",title:"2.7.2. Tetracyclines",level:"3"},{id:"sec_20_3",title:"2.7.3. Statins",level:"3"},{id:"sec_21_3",title:"2.7.4. Renin-Angiotensin System modulators",level:"3"},{id:"sec_22_3",title:"2.7.5. Inhaled corticosteroids",level:"3"},{id:"sec_23_3",title:"2.7.6. Leukotriene-receptor antagonists",level:"3"},{id:"sec_26",title:"3. Conclusions",level:"1"}],chapterReferences:[{id:"ref1",body:'\nAmălinei C, Căruntu ID, Bălan RA. Biology of metalloproteinases. Rom J Morphol Embryol. 2007;48:323–334.\n'},{id:"ref2",body:'\nFanjul-Fernández M, Folgueras AR, Cabrera S, López-Otín C. Matrix metalloproteinases: evolution, gene regulation and functional analysis in mouse model. Biochim Biophys Acta. 2010;1803:3–19. DOI: 10.1016/j.bbamcr.2009.07.004.\n'},{id:"ref3",body:'\nGrzela T, Bikowska B, Litwiniuk M. Matrix metalloproteinases in aortic aneurysm—executors or executioners? In: Grundmann RT, editors. 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Targeting matrix metalloproteinases with intravenous doxycycline in severe sepsis — A randomised placebo-controlled pilot trial. Pharmacol Res. 2015;99:44–51. DOI: 10.1016/j.phrs.2015.05.005.\n'},{id:"ref97",body:'\nLee KS, Jin SM, Kim SS, at al. Doxycycline reduces airway inflammation and hyperresponsiveness in a murine model of toluene diisocyanate-induced asthma. J Allergy Clin Immunol. 2004;113:902–909. DOI: 10.1016/j.jaci.2004.03.008.\n'},{id:"ref98",body:'\nGueders MM, Bertholet P, Perin F et al. A novel formulation of inhaled doxycycline reduces allergen-induced inflammation, hyperresponsiveness and remodeling by matrix metalloproteinases and cytokines modulation in a mouse model of asthma. Biochem Pharmacol. 2008;75:514–526. DOI: 10.1016/j.bcp.2007.09.012.\n'},{id:"ref99",body:'\nAvincsal MO, Ozbal S, Ikiz AO, Pekcetin C, Güneri EA. Effects of topical intranasal doxycycline treatment in the rat allergic rhinitis model. Clin Exp Otorhinolaryngol. 2014;7:106–111. 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DOI: 10.1016/j.rmed.2011.03.020.\n'},{id:"ref114",body:'\nPerng DW, Su KC, Chou KT, et al. Long-acting β2 agonists and corticosteroids restore the reduction of histone deacetylase activity and inhibit H2O2-induced mediator release from alveolar macrophages. Pulm Pharmacol Ther. 2012;25:312–318. DOI: 10.1016/j.pupt.2012.04.001.\n'},{id:"ref115",body:'\nLee SU, Ahn KS, Sung MH, et al. Indacaterol inhibits tumor cell invasiveness and MMP-9 expression by suppressing IKK/NF-κB activation. Mol Cells. 2014;37:585-591. DOI: 10.14348/molcells.2014.0076.\n'},{id:"ref116",body:'\nWang K, Liu CT, Wu YH, et al. Effects of formoterol-budesonide on airway remodeling in patients with moderate asthma. Acta Pharmacol Sin. 2011;32:126–132. DOI: 10.1038/aps.2010.170.\n'},{id:"ref117",body:'\nLin CH, Hsu JY, Hsiao YH, et al. Budesonide/formoterol maintenance and reliever therapy in asthma control: acute, dose-related effects and real-life effectiveness. Respirology. 2015;20:264–272. DOI: 10.1111/resp.12425.\n'},{id:"ref118",body:'\nLanglois A, Ferland C, Tremblay GM, Laviolette M. Montelukast regulates eosinophil protease activity through a leukotriene-independent mechanism. J Allergy Clin Immunol. 2006;118:113–119. DOI: 10.1016/j.jaci.2006.03.010.\n'},{id:"ref119",body:'\nChuang SS, Hung CH, Hua YM et al. Suppression of plasma matrix metalloproteinase-9 following montelukast treatment in childhood asthma. Pediatr Int. 2007;49:918–922. DOI: 10.1111/j.1442-200X.2007.02497.x.\n'},{id:"ref120",body:'\nHsu CH, Hu CM, Lu KH, et al. Effect of selective cysteinyl leukotriene receptor antagonists on airway inflammation and matrix metalloproteinase expression in a mouse asthma model. Pediatr Neonatol. 2012;53:235–244. DOI: 10.1016/j.pedneo.2012.06.004.\n'},{id:"ref121",body:'\nTodorova L, Bjermer L, Miller-Larsson A, Westergren-Thorsson G. Relationship between matrix production by bronchial fibroblasts and lung function and AHR in asthma. Respir Med. 2010;104:1799–1808. DOI: 10.1016/j.rmed.2010.06.015.\n'},{id:"ref122",body:'\nKatainen E, Kostamo K, Virkkula P, et al. Local and systemic proteolytic responses in chronic rhinosinusitis with nasal polyposis and asthma. Int Forum Allergy Rhinol. 2015;5:294–302. DOI: 10.1002/alr.21486.\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Katarzyna Grzela",address:null,affiliation:'
The Medical University of Warsaw, Department of Paediatrics, Pneumonology and Allergology (KG, AS, WZ), and Department of Histology and Embryology (TG), Poland
The Medical University of Warsaw, Department of Paediatrics, Pneumonology and Allergology (KG, AS, WZ), and Department of Histology and Embryology (TG), Poland
The Medical University of Warsaw, Department of Paediatrics, Pneumonology and Allergology (KG, AS, WZ), and Department of Histology and Embryology (TG), Poland
The Medical University of Warsaw, Department of Paediatrics, Pneumonology and Allergology (KG, AS, WZ), and Department of Histology and Embryology (TG), Poland
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Heller, Preeta Dasgupta, Nicolas J. Dorsey, Svetlana P. Chapoval and Achsah D. Keegan",authors:[{id:"64023",title:"Prof.",name:"Achsah",middleName:"Dorsey",surname:"Keegan",fullName:"Achsah Keegan",slug:"achsah-keegan"},{id:"70016",title:"Dr.",name:"Nicola",middleName:null,surname:"Heller",fullName:"Nicola Heller",slug:"nicola-heller"},{id:"70017",title:"Ms.",name:"Preeta",middleName:null,surname:"Dasgupta",fullName:"Preeta Dasgupta",slug:"preeta-dasgupta"},{id:"70019",title:"Ms.",name:"Nicolas",middleName:null,surname:"Dorsey",fullName:"Nicolas Dorsey",slug:"nicolas-dorsey"},{id:"70021",title:"Dr.",name:"Svetlana P.",middleName:null,surname:"Chapoval",fullName:"Svetlana P. Chapoval",slug:"svetlana-p.-chapoval"}]},{id:"31773",title:"Enzymatic and Chemical Modifications of Food Allergens",slug:"enzymatic-and-chemical-modifications-of-food-allergens",signatures:"Dragana Stanić-Vučinić and Tanja Ćirković Veličković",authors:[{id:"69834",title:"Dr.",name:"Dragana",middleName:null,surname:"Stanic-Vucinic",fullName:"Dragana Stanic-Vucinic",slug:"dragana-stanic-vucinic"},{id:"69858",title:"Prof.",name:"Tanja",middleName:null,surname:"Cirkovic Velickovic",fullName:"Tanja Cirkovic Velickovic",slug:"tanja-cirkovic-velickovic"}]},{id:"31774",title:"Characterization of Seafood Proteins Causing Allergic Diseases",slug:"characterization-of-seafood-proteins-causing-allergic-diseases",signatures:"Anas M. Abdel Rahman, Robert J. Helleur, Mohamed F. Jeebhay and Andreas L. Lopata",authors:[{id:"62982",title:"Dr.",name:"Anas",middleName:"M",surname:"Abdel Rahman",fullName:"Anas Abdel Rahman",slug:"anas-abdel-rahman"},{id:"115468",title:"Prof.",name:"Robert",middleName:null,surname:"Helleur",fullName:"Robert Helleur",slug:"robert-helleur"},{id:"115470",title:"Prof.",name:"Mohamed",middleName:"Fareed",surname:"Jeebhay",fullName:"Mohamed Jeebhay",slug:"mohamed-jeebhay"},{id:"115472",title:"Associate Prof.",name:"Andreas",middleName:null,surname:"Lopata",fullName:"Andreas Lopata",slug:"andreas-lopata"}]},{id:"31775",title:"Birch Pollen-Related Food Allergy: An Excellent Disease Model to Understand the Relevance of Immunological Cross-Reactivity for Allergy",slug:"birch-pollen-related-food-allergy-an-excellent-disease-model-to-understand-the-relevance-of-immunolo",signatures:"Brinda Subbarayal, Marija Geroldinger-Simic and Barbara Bohle",authors:[{id:"67762",title:"Prof.",name:"Barbara",middleName:null,surname:"Bohle",fullName:"Barbara Bohle",slug:"barbara-bohle"},{id:"68331",title:"MSc.",name:"Brinda",middleName:null,surname:"Subbarayal",fullName:"Brinda Subbarayal",slug:"brinda-subbarayal"},{id:"68332",title:"Dr.",name:"Marija",middleName:null,surname:"Geroldinger-Simic",fullName:"Marija Geroldinger-Simic",slug:"marija-geroldinger-simic"}]},{id:"31776",title:"Anaphylaxis: Etiology, Clinical Manifestations, Diagnosis and Management",slug:"anaphylaxis-etiology-clinical-manifestations-diagnosis-management",signatures:"Aslı Gelincik and Suna Büyüköztürk",authors:[{id:"68677",title:"Dr.",name:"Asli",middleName:null,surname:"Gelincik",fullName:"Asli Gelincik",slug:"asli-gelincik"},{id:"69179",title:"Prof.",name:"Suna",middleName:null,surname:"Buyukozturk",fullName:"Suna Buyukozturk",slug:"suna-buyukozturk"}]},{id:"31777",title:"Allergic Airway Inflammation",slug:"allergic-airway-inflammation",signatures:"Gabriel Morán, Claudio Henriquez and Hugo Folch",authors:[{id:"64090",title:"Dr.",name:"Gabriel",middleName:null,surname:"Morán",fullName:"Gabriel Morán",slug:"gabriel-moran"},{id:"129881",title:"Dr.",name:"Claudio",middleName:null,surname:"Henriquez",fullName:"Claudio Henriquez",slug:"claudio-henriquez"},{id:"129882",title:"Dr.",name:"Hugo",middleName:null,surname:"Folch",fullName:"Hugo Folch",slug:"hugo-folch"}]},{id:"31778",title:"Asthma and Sensitization Pattern in Children",slug:"asthma-and-sensitization-pattern-in-children",signatures:"Ute Langen",authors:[{id:"64581",title:"Dr.",name:"Ute",middleName:null,surname:"Langen",fullName:"Ute Langen",slug:"ute-langen"}]},{id:"31779",title:"Wheezing Infant",slug:"wheezing-infant",signatures:"Yukinori Yoshida, Tomoshige Matsumoto, Makoto Kameda, Tomoki Nishikido, Isamu Takamatsu and Satoru Doi",authors:[{id:"70150",title:"Dr.",name:"Tomoshige",middleName:null,surname:"Matsumoto",fullName:"Tomoshige Matsumoto",slug:"tomoshige-matsumoto"},{id:"97712",title:"Dr.",name:"Yukinori",middleName:null,surname:"Yoshida",fullName:"Yukinori Yoshida",slug:"yukinori-yoshida"},{id:"103503",title:"Dr.",name:"Makoto",middleName:null,surname:"Kameda",fullName:"Makoto Kameda",slug:"makoto-kameda"},{id:"103522",title:"Dr.",name:"Tomoki",middleName:null,surname:"Nishikido",fullName:"Tomoki Nishikido",slug:"tomoki-nishikido"},{id:"103679",title:"Dr.",name:"Isamu",middleName:null,surname:"Takamatsu",fullName:"Isamu Takamatsu",slug:"isamu-takamatsu"},{id:"103682",title:"Dr.",name:"Satoru",middleName:null,surname:"Doi",fullName:"Satoru Doi",slug:"satoru-doi"}]},{id:"31780",title:"Comorbidities of Allergic Rhinitis",slug:"co-morbidities-of-allergic-rhinitis",signatures:"Doo Hee Han and Chae-Seo Rhee",authors:[{id:"65555",title:"Prof.",name:"Chae-Seo",middleName:null,surname:"Rhee",fullName:"Chae-Seo Rhee",slug:"chae-seo-rhee"},{id:"68110",title:"Dr.",name:"Doo Hee",middleName:null,surname:"Han",fullName:"Doo Hee Han",slug:"doo-hee-han"}]},{id:"31781",title:"Allergy and Benign Lesions of the Vocal Cord Mucosa",slug:"the-role-of-allergy-in-the-etiology-of-reinke",signatures:"Alenka Kravos",authors:[{id:"65009",title:"MSc.",name:"Alenka",middleName:null,surname:"Kravos",fullName:"Alenka Kravos",slug:"alenka-kravos"}]},{id:"31782",title:"Drug Hypersensitivity",slug:"cellular-tests-in-the-diagnosis-of-drug-hypersensitivity",signatures:"María L. Sanz, Cristobalina Mayorga, Ruben Martínez-Aranguren and Pedro M. Gamboa",authors:[{id:"69766",title:"Prof.",name:"María L",middleName:null,surname:"Sanz",fullName:"María L Sanz",slug:"maria-l-sanz"}]},{id:"31783",title:"Diagnosis and Management of Cows' Milk Protein Allergy in Infants",slug:"diagnosis-and-management-of-cows-milk-protein-allergy-in-infants",signatures:"Elisabeth De Greef, Thierry Devreker, Bruno Hauser and Yvan Vandenplas",authors:[{id:"68130",title:"Prof.",name:"Yvan",middleName:null,surname:"Vandenplas",fullName:"Yvan Vandenplas",slug:"yvan-vandenplas"},{id:"126163",title:"Dr.",name:"Gigi",middleName:null,surname:"Veereman-Wauters",fullName:"Gigi Veereman-Wauters",slug:"gigi-veereman-wauters"},{id:"127716",title:"Dr.",name:null,middleName:null,surname:"Veereman-Wauters",fullName:"Veereman-Wauters",slug:"veereman-wauters"}]},{id:"31784",title:"Natural Rubber Latex Allergy",slug:"natural-rubber-latex-allergy",signatures:"Ana Maria Sell and Jeane Eliete Laguila Visentainer",authors:[{id:"63282",title:"PhD.",name:"Jeane",middleName:"Eliete Laguila",surname:"Visentainer",fullName:"Jeane Visentainer",slug:"jeane-visentainer"},{id:"64275",title:"Dr.",name:"Ana",middleName:"Maria",surname:"Sell",fullName:"Ana Sell",slug:"ana-sell"}]},{id:"31785",title:"Psychological Factors in Asthma and Psychoeducational Interventions",slug:"psychological-factors-in-asthma-and-psychoeducational-interventions",signatures:"Lia Fernandes",authors:[{id:"67367",title:"Prof.",name:"Lia",middleName:null,surname:"Fernandes",fullName:"Lia Fernandes",slug:"lia-fernandes"}]},{id:"31786",title:"Obesity, Diet, Exercise and Asthma in Children",slug:"diet-obesity-exercise-and-asthma-in-children",signatures:"Luis Garcia-Marcos and Manuel Sanchez-Solis",authors:[{id:"67592",title:"Prof.",name:"Luis",middleName:null,surname:"Garcia-Marcos",fullName:"Luis Garcia-Marcos",slug:"luis-garcia-marcos"}]},{id:"31787",title:"Asthma and Health Related Quality of Life in Childhood and Adolescence",slug:"health-related-quality-of-life-in-children-with-asthma",signatures:"Esther Hafkamp-de Groen and Hein Raat",authors:[{id:"65735",title:"Dr.",name:"Hein",middleName:null,surname:"Raat",fullName:"Hein Raat",slug:"hein-raat"},{id:"134155",title:"Dr.",name:"Esther",middleName:null,surname:"Hafkamp - de Groen",fullName:"Esther Hafkamp - de Groen",slug:"esther-hafkamp-de-groen"}]},{id:"31788",title:"Specific Immunotherapy and Central Immune System",slug:"specific-immunotherapy-and-central-immune-system-",signatures:"Celso Pereira, Graça Loureiro, Beatriz Tavares and Filomena Botelho",authors:[{id:"66336",title:"Prof.",name:"Celso",middleName:null,surname:"Pereira",fullName:"Celso Pereira",slug:"celso-pereira"},{id:"66342",title:"Dr.",name:"Beatriz",middleName:null,surname:"Tavares",fullName:"Beatriz Tavares",slug:"beatriz-tavares"},{id:"66343",title:"Dr.",name:"Graça",middleName:null,surname:"Loureiro",fullName:"Graça Loureiro",slug:"graca-loureiro"},{id:"66344",title:"Prof.",name:"Filomena",middleName:null,surname:"Botelho",fullName:"Filomena Botelho",slug:"filomena-botelho"}]},{id:"31789",title:"β2-Adrenoceptor Agonists and Allergic Disease: The Enhancing Effect of β2-Adrenoceptor Agonists on Cytokine-Induced TSLP Production by Human Lung Tissue Cells",slug:"beta2-adrenoceptor-agonists-and-allergic-disease-the-enhancing-effect-of-beta2-adrenoceptor-agonists",signatures:"Akio Matsuda and Kyoko Futamura",authors:[{id:"63896",title:"Dr.",name:"Akio",middleName:null,surname:"Matsuda",fullName:"Akio Matsuda",slug:"akio-matsuda"},{id:"66899",title:"Dr.",name:"Kyoko",middleName:null,surname:"Futamura",fullName:"Kyoko Futamura",slug:"kyoko-futamura"}]},{id:"31790",title:"Microbiota and Allergy: From Dysbiosis to Probiotics",slug:"microbiota-and-allergy-from-dysbiosis-to-probiotics",signatures:"Anne-Judith Waligora-Dupriet and Marie-José Butel",authors:[{id:"65930",title:"Dr.",name:"Anne-Judith",middleName:null,surname:"Waligora-Dupriet",fullName:"Anne-Judith Waligora-Dupriet",slug:"anne-judith-waligora-dupriet"},{id:"69522",title:"Prof.",name:"Marie-José",middleName:null,surname:"Butel",fullName:"Marie-José Butel",slug:"marie-jose-butel"}]},{id:"31791",title:"Natural Products and Dermatological Hypersensitivity Diseases",slug:"naturally-sourced-bioactives-are-a-promising-source-of-novel-allergy-therapies",signatures:"Clayton MacDonald and Marianna Kulka",authors:[{id:"63821",title:"Dr.",name:"Marianna",middleName:null,surname:"Kulka",fullName:"Marianna Kulka",slug:"marianna-kulka"}]},{id:"31792",title:"Preventive Phytotherapy of Anaphylaxis and Allergic Reactions[MSOffice1]",slug:"preventive-phytotherapy-of-anaphylactic-shock",signatures:"Elaine A. Cruz, Michelle F. Muzitano, Sonia S. Costa and Bartira Rossi-Bergmann",authors:[{id:"64710",title:"Prof.",name:"Bartira",middleName:null,surname:"Rossi-Bergmann",fullName:"Bartira Rossi-Bergmann",slug:"bartira-rossi-bergmann"},{id:"119635",title:"Dr.",name:"Elaine",middleName:null,surname:"Cruz",fullName:"Elaine Cruz",slug:"elaine-cruz"}]},{id:"31793",title:"Cissampelos sympodialis (Menispermaceae): A Novel Phytotherapic Weapon Against Allergic Diseases?",slug:"cissampelos-sympolialis-menispermaceae-a-novel-phytotherapic-weapon-against-allergic-diseases-",signatures:"M.R. Piuvezam, C.R. Bezerra-Santos, P.T. Bozza, C. Bandeira-Melo, G. Vieira and H.F. Costa",authors:[{id:"64380",title:"Dr.",name:"Marcia",middleName:"Regina",surname:"Piuvezam",fullName:"Marcia Piuvezam",slug:"marcia-piuvezam"},{id:"117360",title:"Dr.",name:"Claudio",middleName:null,surname:"Bezerra-Santos",fullName:"Claudio Bezerra-Santos",slug:"claudio-bezerra-santos"},{id:"117362",title:"Dr.",name:"Christianne",middleName:null,surname:"Bandeira-Melo",fullName:"Christianne Bandeira-Melo",slug:"christianne-bandeira-melo"},{id:"117363",title:"MSc.",name:"Giciane",middleName:null,surname:"Vieira",fullName:"Giciane Vieira",slug:"giciane-vieira"},{id:"117364",title:"MSc.",name:"Hermann",middleName:null,surname:"Costa",fullName:"Hermann Costa",slug:"hermann-costa"},{id:"117365",title:"Dr.",name:"Patricia",middleName:null,surname:"Bozza",fullName:"Patricia Bozza",slug:"patricia-bozza"}]},{id:"31794",title:"Derived Products of Helminth in the Treatment of Inflammation, Allergic Reactions and Anaphylaxis",slug:"anaphylaxis-an-overview-of-immune-mechanisms-and-therapeutic-strategies-using-helminth-products",signatures:"C.A. Araujo and M.F. Macedo-Soares",authors:[{id:"67870",title:"PhD.",name:"Maria Fernanda",middleName:null,surname:"Macedo Soares",fullName:"Maria Fernanda Macedo Soares",slug:"maria-fernanda-macedo-soares"},{id:"70139",title:"Dr.",name:"Claudia",middleName:null,surname:"Araujo",fullName:"Claudia Araujo",slug:"claudia-araujo"}]},{id:"31795",title:"Parasite-Derived Proteins Inhibit Allergic Specific Th2 Response",slug:"parasite-derived-proteins-inhibit-allergic-specific-th2-response-",signatures:"Hak Sun Yu",authors:[{id:"65987",title:"Prof.",name:"Hak Sun",middleName:null,surname:"Yu",fullName:"Hak Sun Yu",slug:"hak-sun-yu"}]},{id:"31796",title:"Pharmaceutical Treatment of Asthma Symptoms in Elite Athletes - Doping or Therapy",slug:"pharmaceutical-treatment-of-asthma-symptoms-in-elite-athletes-doping-or-therapy",signatures:"Jimmi Elers and Vibeke Backer",authors:[{id:"71053",title:"Dr",name:null,middleName:null,surname:"Backer",fullName:"Backer",slug:"backer"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"67131",title:"Different Pretreatment Methods of Lignocellulosic Biomass for Use in Biofuel Production",doi:"10.5772/intechopen.84995",slug:"different-pretreatment-methods-of-lignocellulosic-biomass-for-use-in-biofuel-production",body:'\n
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1. Introduction
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We are living in a world of many challenges such as climate changes, polluted environment, resource depletion, and increasing demand for fuel. The use of oil reserves to fulfill our need of fuel has caused many drastic challenges from energy security to change in temperature. Rapid industrialization has increased the demand of petroleum products and consequently has raised the monopoly of few countries, which can manipulate petroleum price and create instability. This may also create environmental problems by emission of greenhouse gases and subsequently effect on climate change. The most important source of energy is petroleum that is largely used in transportation and industries; therefore, viability of liquid fuel is enhanced. As the environmental issues are growing, more research is being conducted to address the problems. The search for alternative source of petrol that is less costly with minimal environmental effects has become the center of attention. For instance, biomass is considered as a sustainable resource that can be utilized in large-scale production of biofuel that can be utilized as an alternative source of fuel and may present solution to environmental problems. Furthermore, relying on fossil fuel could be detrimental as it has been predicted of its depletion by 2050. The total annual primary production of biomass is over 100 billion tonnes of carbon per year, and the energy reserve per metric tonne of biomass is between 1.5E3 and 3E3 kW hours that is sufficient to cater the needs of the world energy requirements [1].
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Bioenergy products like bioethanol, biohydrogen, and biodiesel can be obtained from lignocellulose biomass which is considerably large renewable bioresource and obtained from plants. The term “lignocellulosic biomass” is defined as lignin, cellulose, and hemicellulose that constitute the plant cell wall. Strong cross-linking associations are present between these components that cause hindrance in the breakdown of plant cell wall. Polysaccharides and lignin are cross-linked via ester and ether linkages [2, 3, 4]. Microfibrils that are formed by cellulose, hemicellulose, and lignin help in the stability of plant cell wall structure [5, 6].
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Lignocellulose was first produced from food crop such as corn, oilseed, and sugarcane. But the use of edible feedstock for bioenergy products formation is being discouraged to prevent the rise in food competition. Thus, second-generation biofuels are obtained from plants wastes to avoid competition of land and water resources between energy crops and food crops. Currently, lignocellulose is being produced from wood residues, agricultural residues, food industry residue, grasses, domestic wastes, municipal solid wastes, and nonfood seeds [7, 8, 9]. The lignocellulose wastes (LCW) are largest renewable bioresource reservoir on earth that is being wasted as pre and postharvest agricultural wastes. Thus, many steps need to be adopted for use of these renewable resources for the production of bioenergy products. Recovery of many products like enzymes, methane, activated carbon, lipids, resins, methane, carbohydrates, surfactants, resins, organic acids, ethanol, amino acids, degradable plastic composites, biosorbents, biopesticides, and biopromoters can be achieved by utilizing LCW. The added benefits of using LCW besides recovery of different products are the removal of LCW waste from the environment. Also, utilization of LCW eliminates the use of food for bioethanol production. The US government has planned the production of 21 billion gallon of biofuels by 2022 [2, 5]. Biofuel production from lignocellulosic biomass reduces the emission of greenhouse gases.
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Pretreatment brings physical, biological, and chemical changes to biomass structure; therefore, it is very important to consider the type of pretreatment. In order to break down the hindrance caused by strong association within the cell wall, pretreatment is an important step which can increase the availability of lignocellulosic biomass for cellulase enzymes, their digestibility, and product yield. Before subjection to enzymatic hydrolysis, pretreatment of biomass can increase the rate of hydrolysis by 3–10-fold. Pretreatment of LCW is not an easy step as it seems after the installation of power generator; pretreatment is the second most costly process at industrial level. In crystalline cellulose, the disruption of hydrogen bonds, cross-linked matrix disruption, and increase in porosity as well as surface area of cellulose are the three tasks that are performed via a suitable pretreatment methods. The outcome of pretreatment also differs due to the difference in the ratio of cell wall components [10, 11]. The option to use dilute acid pretreatment method is more effective against poplar tree bark or corn as compared to the same method used for sweet gum bark or cornstalks. Few requirements of an effective, efficient, and economically suitable pretreatment process that including use of cheap chemicals, very less consumption of chemicals, prevention of hemicellulose and cellulose from denaturation, minimal energy requirement and consumption, cost-effective size reduction process, and reactive cellulosic fiber production are the factors that need to be considered for pretreatment. There are several methods of pretreatment that can be divided into four categories, namely, chemical, physical, biological, and physiochemical pretreatment [12, 13, 14, 15].
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2. Physical methods
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Pore size and surface area of lignocellulosic biomass can be increased, whereas crystallinity and degree of polymerization of cellulose can be decreased with the application of physical methods. Physical pretreatments include milling, sonication, mechanical extrusion, ozonolysis, and pyrolysis.
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2.1 Milling
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On the inherent ultrastructure of cellulose and degree of crystallinity, milling can be performed to render lignocelluloses more amenable to cellulases. Cellulases are enzyme that catalyze cellulose, but for the catalysis and best results, the substrate availability needs to be enhanced for optimized functioning of the enzymes. Before the subjection of the LCW to enzymatic hydrolysis, milling and size reduction of the lignocellulosic matter should be performed. Milling process has several types like ball milling, colloid milling, vibro-energy milling, hammer milling, and two-roll milling. For wet material, colloid mill, dissolver, and fibrillator are suitable, whereas for dry materials hammer mill, extruder, cryogenic mill, and roller mill are used. For both wet and dry material, ball milling can be used. For waster paper, hammer milling is the most suitable pretreatment option. Enzymatic degradation can be improved by milling as it reduces the degree of crystallinity and material size. Up to 0.2 mm reduction in particle size can be seen by milling and grinding. Reduction in particle size of biomass can be achieved up to a certain limit; beyond that limit reduction in particle size does not effect in the pretreatment procedure. Corn stover with small particle size, i.e., from 53 to 75 μm, is more productive as compared to large particle size corn stover ranging from 475 to 710 μm. The difference in particle size shows that productivity can significantly affect the pretreatment process. Ball milling causes a massive drop in crystallinity index from 4.9 to 74.2% which makes this process more suitable for saccharification of straw at mild hydrolytic conditions with more production of fermentable sugars [12, 16, 17, 18]. For better results of hydrolysis, milling can be used in combination with enzymatic hydrolysis. Mechanical action, mass transfer, and enzymatic hydrolysis can be achieved at the same time when two methods are combined. A number of ball beads in bill mill reactor play a crucial role in the α-cellulose hydrolysis, as less enzyme loading is required, and 100% rate of hydrolysis can be achieved in comparison to pretreatment of biomass that is carried without the use of milling procedure. Highest hydrolysis rate with high yield of reducing sugar was obtained when rice straw was put into fluidized bed opposed jet mill for fine grinding after cutting, steam explosion, and pulverization. For pretreatment of biomass, ball milling is an expensive option in terms of energy consumption, which is a huge disadvantage at industrial scale. Also, incapability of milling for removing lignin makes it a less suitable option as enzyme accessibility to the substrate is reduced in the presence of lignin. Reduction in crystallinity, degree of polymerization, and increase in surface area can be effected by the type of biomass, type of milling used for pretreatment, and duration of the milling process [19, 20, 21].
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For improving digestibility and reducing crystallinity, vibratory ball milling is very effective. Low energy consumption has an important advantage of using wet disk milling which produces fibers that improve hydrolysis of cellulose, whereas hammer milling produces finer bundles. Due to this reason milling is not preferred when wet disk milling is available [22, 23]. Other study results of conventional ball and disk milling are compared. With the use of conventional ball milling, maximum yields of xylose and glucose were obtained, i.e., 54.3 and 89.4%, respectively [24]. Wet milling produces less yield, but it has the advantage of not producing inhibitors and very low energy consuming capability. An increase of 110% in enzymatic hydrolysis was achieved when wet milling was combined with alkaline pretreatment. Optimum parameters for wet milling pretreatment of corn stover were 10 mm diameter 20 steel balls, 1:10 solid-to-liquid ratio, 350 rpm/min speed, and 0.5 mm particle size [25] (Figures 1 and 2).
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Figure 1.
Colloid milling (Pharmapproach.com).
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Figure 2.
Hammer milling (Solidswiki.com).
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2.2 Microwave
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Commonly used method for plant biomass pretreatment is microwave irradiation. This pretreatment method has several advantages that include ease of pretreatment, increased heating capacity, short processing time, minimal generation of inhibitors, and less energy requirement. Microwave irradiation in closed container was first reported in 1984 by team of researchers from Kyoto University, Japan. They treated sugarcane bagasse, rice straw, and rice hulls with microwaves in the presence of water. The conditions used for microwave treatment include glass vessels of 50 mL, 2450 MHz energy, and 2.4 kW microwave irradiation [26]. Classical pretreatment methods were carried out at high pressure and temperatures. Chemical interactions between lignocellulosic material break as a result of high temperature, thus increasing substrate availability to the enzymes. Under high-pressure steam injection or indirect heat injection, high temperature between 160 and 250°C is provided to lignocellulosic material in conventional heating methods. However, in order to prevent temperature gradients, crushing of lignocellulosic material into small particles is needed. To avoid large temperature gradients, microwave is a good choice as it uniformly distributes heat which also avoids degradation of lignocellulosic material into humic acid and furfural. For effective degradation, microwave irradiation is combined with mild alkali treatment. Sugar yield of 70–90% from switch grass was obtained from alkali and irradiation combined pretreatment [27]. As microwave irradiation is performed at high temperature, therefore, closed containers are required to achieve high temperature. Three properties, namely, penetration, reflection, and absorbance are exhibited by microwave. Microwave passes through glass and plastic, absorbed by water and biomass, whereas microwaves are reflected by metals. Based on these properties, microwave reactors can be divided into two types, one that allows the passage of microwaves, whereas the other kind reflects the microwaves. Glass or plastic is the building material of the first type of microwave reactors, whereas the second types of reactors are composed of steel. Through quartz windows, microwaves can enter into the reactor as these are placed in the reactor. Closed, sealable, pressure-resistant glass tube container having gasket made up of Teflon can be used for the high temperature, i.e., 200°C, for microwave irradiation pretreatment. Sensors are used to control and ensure temperature inside the microwave. Teflon-coated sensors are a good choice because of the thermostability, corrosion-free nature, and zero absorbance properties. In a microwave oven, Teflon vessels are used by some scientists due to its advantageous properties [28, 29]. Normally vessel sizes vary from 100 mL to several hundred milliliters. A 650 mL vessel with 318 mm length, connected nitrogen bottle, gauges, and thermometers are installed on the top of the microwave that was designed by Chen and Cheng [30]. Besides the glass vessels and stainless steel tanks with temperature and pressure sensors, automatic controlling system for microwave input and mechanical stirrer are also used (Figure 3).
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Figure 3.
Microwave irradiation (Researchgate.net).
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2.3 Mechanical extrusion
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When materials that can pass through a defined cross section die, it appears out with the fixed definite profile. This is the extrusion process which is known for sugar recovery from biomass. Adaptability to modifications, no degradation products, controllable environment, and high throughput are few advantages related to mechanical extrusion pretreatment process. Single screw extruder and twin screw extruder are two types of extruders.
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Single screw extruder is based on three screw elements, forward, kneading, and reverse. With the minimum shearing and mixing, bulk material of varying pitches and lengths can be transported by forward screw element. Prominent mixing and shearing effect is produced by kneading screw elements with weak forward conveying effect, whereas the use of immense mixing and shearing involves material that is pushed back by reverse screw elements. A screw configuration is defined by the arrangement of different stagger angels, lengths spacing, pitches, and positions. Twin screw extruder can accomplish multiple tasks at the same time like mixing, shearing, grinding, reaction, drying, and separation. High enzymatic hydrolysis rates are achieved by the use of single and twin screw extruders. Different parameters like speed of screw, temperature of barrel, and compression ratio can significantly affect recovery of sugars. Short-time extruders provide fast heat transfer, proper mixing, and increased shear. When material passed through the extruder barrel, structure of biomass is disturbed, exposing more surface for enzymatic hydrolysis [31, 32, 33]. During extrusion process, lignocellulosic material can be treated with alkali or acid in order to increase sugar recovery. Acidic treatment is less preferred than alkali because of the corrosion caused by acid to the extruder material. Corrosion problem can be solved by the use of AL6XN alloy for barrel fabrication and screws of extruder. With less carbohydrate degradation and role in the delignification, alkali treatment is suitable for lignocellulosic material. Sodium hydroxide is most commonly used to break ester linkages and solubilization of lignins and hemicelluloses. Alkali treatment can be applied by addition of alkali using volumetric pump into the extruder or by soaking the lignocellulosic material in alkali at room temperature [31, 34, 35] (Figure 4).
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Figure 4.
Twin screw extruder (Researchgate.net).
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2.4 Pyrolysism
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For the production of bio oil from biomass, process of pyrolysis is used. Pyrolysis is a thermal degradation of lignocellulosic biomass at very high temperature without the presence of oxidizing agent. At temperature ranging between 500 and 800°C, pyrolysis was performed. Rapid decomposition of cellulose resulted in the formation of products like pyrolysis oil and charcoal [36]. Based on temperature, pyrolysis pretreatment process is divided into fast and low pyrolysis. Certain factors affect the end products like biomass characteristics, reaction parameters, and type of pyrolysis. Due to high-value energy-rich product formation, easy transport management retrofitting, combustion, storage, and flexibility in utilization and marketing, thermal industries are adapting to the process of pyrolysis. Presence of oxygen and less temperature increase the efficiency of this process. A study on the bond cleavage rate of cellulose was carried out in the presence of nitrogen and oxygen. During the process of pyrolysis, breakage of 7.8 × 109 bonds/min/g cellulose in the presence of oxygen and breakdown of 1.7 × 108 bonds/min/g cellulose in the presence of nitrogen at 25°C were observed. In order to obtain more efficiency and results, microwave-assisted pyrolysis is preferred due to the microwave dielectric heating [37]. Thermochemical conversion of biomass into biofuels can be performed via three technologies, gasification, pyrolysis, and direct combustion [38]. Different yields of products from pyrolysis are due to different modes of pyrolysis. Bio oil is a mixture of polar organics and water. Pyrolysis is used where bio oil production is required. Fast pyrolysis in a controlled environment leads to the formation of liquid products (fuels). Torrefaction is an emerging technique which is also known as mild pyrolysis. It differs from pyrolysis with reference to thermochemical process that is carried out at temperature range between 200 and 300°C. Partial decomposition of biomass occurs in this process, and ultimate product obtained is terrified biomass. Whereas, in the process of pyrolysis, plant biomass is decomposed into vapor, aerosols, and char. Torrefaction has been categorized into two categories based on dry and wet torrefaction.
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Dry torrefaction needs an inert environment and completely dry biomass and normal atmospheric pressure. Biochar is the major product in this type of biomass pretreatment. Hydrothermal carbonization and hydrothermal torrefaction are other terminologies used for wet torrefaction. Unlike dry torrefaction, pressurized vessel of water is used to carry out the pretreatment. Biomass used for wet torrefaction contains moisture content, but after torrefaction, a drying process is necessary in this type of torrefaction. A pressure between 1 and 250 MPa is required to carry out wet torrefaction. Biomass used during wet torrefaction pretreatment produces hydro-char as a main product [39].
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2.5 Pulse electric field (PEF)
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In this method, pores are created in the cell membrane due to which cellulose exposes to such agents that cause its breakdown by entering into the cell. High voltage ranging between 5.0 and 20.0 kV/cm is applied in a sudden burst to biomass for nano- to milliseconds. Sample was placed between two parallel plate electrodes, and the strength of electric field is given as E = V/d, where V and d are voltage and distance, respectively, between plate electrodes. Dramatic increase in mass permeability and tissue rapture occurred on the application of electric field. Electric pulses are applied, generally in the form of square waves or exponential decay. Setup of pulse electric field consisted of pulse generator, control system, data acquisition system, and material handling equipment [40, 41]. At ambient temperatures, the treatment can be performed at low energy. Another advantage of this treatment is the simple design of the instrument. Short duration of pulse time saves the effort and energy [42, 43]. Pulse electric field pretreatment was applied to pig manure and waste activated sludge by Author et al. [44]. As compared to untreated manure and sludge, 80% methane from manure and twofold increase in methane production from sludge were recorded in the study. A PEF system was designed and developed by Kumar et al. [45] that consisted of high-voltage power supply, switch circuit, a function generator, and sample holder. Neutral red dye was used to study the changes in the structure of cellulose by PEF pretreatment. Function generator drives the transistor present in the switching circuit; when pulse is applied by function generator to the switching circuit, switching circuit is turned on. Switching circuit is then transferred to the high voltage across the sample holder. So, by using function generator pulses of desired shape, width and high voltage can be applied to the sample. By using this setup, effects were observed on switch grass and wood. Results showed that at ≥8 kV/cm, switch grass showed high neutral red uptake. At low field strength, structural changes are less likely to occur. Electroporation through pulsed electric field is greatly affected by two parameters, pulse duration and electric field strength. Irreversible electroporation at >4 kV/cm with pulse duration in millisecond and ≥ 10 kV/cm with microsecond pulse duration was observed in Chlorella vulgaris which showed that pulse duration with a difference in micro- and milliseconds range can effect electroporation. Pulse electric field can increase hydrolysis rate by exposing cellulose to catalytic agents [40, 41, 46] (Figure 5).
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Figure 5.
Pulse electric field (Intechopen.com).
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3. Chemical pretreatments
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3.1 Acid pretreatment
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In this pretreatment, acids are used to pretreat lignocellulosic biomass. The generation of inhibitory products in the acid pretreatment renders it less attractive for pretreatment option. Furfurals, aldehydes, 5-hydroxymethylfurfural, and phenolic acids are the inhibitory compounds that are generated in huge amount in acid pretreatment. There are two types of acid treatments based on the type of end application. One treatment type is of short duration, i.e., 1–5 min, but high temperature > 180°C is used, and the second treatment type is of long duration, i.e., 30–90 min, and low temperature < 120°C is utilized. Due to hydrolysis by acid treatment, separate step of hydrolysis of biomass can be skipped, but to remove acid, washing is required before the fermentation of sugars [43, 47]. For acid pretreatment, such reactors are required that show resistance to corrosive, hazardous, and toxic acids; therefore, acid pretreatment is very expensive. Flow through, percolation, shrinking-bed, counter current rector, batch, plug flow are different types of rectors that have been developed. For enhancing economic feasibility of acid pretreatment, recovery of concentrated acid at the end of the treatment is an important step.
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To treat lignocellulosic biomass, concentrated acids are also used. Most commonly used acids are sulfuric acid or hydrochloric acid. In order to improve the process of hydrolysis for releasing fermentable sugars from lignocellulosic biomass, acid pretreatment can be given. For poplar, switch grass, spruce, and corn stover, sulfuric acid pretreatment is commonly used. Reducing sugars of 19.71 and 22.93% were produced as a result of the acid pretreatment of Bermuda grass and rye, respectively. In percolation reactor, pretreatment of rice straw was carried out in two stages using aqueous ammonia and dilute sulfuric acid. When ammonia is used, 96.9% reducing sugar yield was obtained, while 90.8% yield was obtained in case of utilization of dilute acid. Eulaliopsis binate is a perennial grass and yielded 21.02% sugars, 3.22% lignin, and 3.34% acetic acid, and inhibitors in very less amount are produced when treated with dilute sulfuric acid [48, 49]. At 4 wt% concentration of sulfuric acid, pretreatment is preferred because of less cost and more effectiveness of the process. Dilute sulfuric acid causes biomass hydrolysis and then further breakdown of xylose into furfural is achieved. High temperature favors hydrolysis by dilute sulfuric acid [50]. Removal of hemicellulose is important to increase glucose yield from cellulose, and dilute sulfuric acid is very effective to achieve this purpose. It is necessary for an economical biomass conversion to achieve high xylan-to-xylose ratio. One-third of the total carbohydrate is xylan in most lignocellulosic materials. There are two types of dilute acid pretreatments, one is characterized by high temperature, continuous flow process for low solid loadings, and the other one is with low temperature, batch process and high solid loadings. Temperature and solid loadings for the first type are >160°C and 5–10%, respectively, and for the second type, temperature and solid loadings are around<160°C and 10–40%, respectively [51, 52].
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Besides sulfuric acid and hydrochloric acid, other acids like oxalic acid and maleic acid are also used for the pretreatment of lignocellulosic biomass. Oxalic and maleic acids have high pKa value and solution pH as compared to sulfuric acid. Because of having two pKa values, dicarboxylic acids hydrolyze biomass more efficiently than sulfuric acid and hydrochloric acid. Other advantages include less toxicity to yeast, no odor, more range of pH and temperature for hydrolysis, and no hampering of glycolysis. Maleic acid has khyd/kdeg, due to which hydrolysis of cellulose to glucose is preferred over glucose breakdown. Effects of oxalic, sulfuric, and maleic acid pretreatment on biomass at the same combined severity factor (CSF) were determined [53]. The use of maleic acid produces high concentration of xylose and glucose as compared to oxalic acid.
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3.2 Alkali pretreatment
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Apart from acids, few bases are also used for pretreatment of biomass. Lignin contents greatly affected the result of alkaline treatment. As compared to other pretreatment methods, alkali treatment requires less pressure and temperature and ambient condition, but alkali pretreatment needs time in days and hours. Degradation of sugar in alkali treatment is less than that by acid treatment, and also the removal and recovery of caustic salt are possible and easy in case of alkali treatment. Ammonium, sodium, calcium, and potassium hydroxides are used for alkaline pretreatment, but among these sodium hydroxide is the most commonly used alkaline pretreatment agent, whereas calcium hydroxide is the cheapest yet effective among all other alkali agents for pretreatment. By neutralizing calcium with carbon dioxide, calcium can be recovered easily in form of insoluble calcium carbonate. Using lime kiln technology, calcium hydroxide can be regenerated. Apparatus required for alkali pretreatment is basically temperature controller, a tank, CO2 scrubber, water jacket, manifold for water and air, pump, tray, frame, temperature sensor, and heating element. The first step of pretreatment consists of making lime slurry with water. The next step is spraying of this slurried lime on biomass; after spray, store the biomass for hours or, in some case, days. Contact time can be reduced by increasing temperature [54, 55, 56, 57]. Crystallinity index increases in lime pretreatment because of the removal of lignin and hemicellulose. Structural features resulting from lime pretreatment affect the hydrolysis of pretreated biomass. Correlation of three structural factors, viz., lignin, acetyl content and crystallinity, and enzymatic digestibility, was reported by Chang and Holtzapple [58]. He concluded that (1) regardless of crystallinity and acetyl content, in order to obtain high digestibility, extensive delignification is enough. (2) Parallel barriers to hydrolysis are removed by delignification and deacetylation. (3) Crystallinity does not affect ultimate sugar yield; however, it plays some role in initial hydrolysis. It is evident from these points that lignin content should be reduced to 10% and all acetyl groups should be removed by an effective pretreatment process. Thus in exposing cellulose to enzymes, alkaline pretreatment plays an important role. By increasing enzyme access to cellulose and hemicellulose and eliminating nonproductive adsorption sites, lignin removal can play its role in increasing effectiveness of enzyme.
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3.3 Organosolv
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Aqueous organic solvents like methanol, acetone, ethanol, and ethylene glycol are used in this method with specific conditions of temperature and pressure. Organosolv pretreatment is usually performed in the presence of salt catalyst, acid, and base. The biomass type and catalyst involved decide the temperature of pretreatment, and it can go up to 200°C. Lignin is a valuable product, and to extract lignin this process is used mainly. Cellulose fibers are exposed when lignin is removed, which leads to more hydrolysis. During organosolv pretreatment, fractions and syrup of cellulose and hemicellulose, respectively, are also produced. There are certain variable factors like catalyst type, temperature, and concentration of solvent and reaction time which affects the characteristics of pretreated biomass like crystallinity, fiber length, and degree of polymerization. Inhibitor formation is triggered by long reaction, high temperature, and acid concentrations [59, 60]. In a study by Park et al. [61], effect of different catalyst was checked for the production of ethanol and among sulfuric acid, sodium hydroxide, and magnesium sulfate, and sulfuric acid was found to be most effective in ethanol production, but for enhancing digestibility the use of sodium hydroxide is proven to be effective. Sulfuric acid is a good catalyst, but its toxicity and inhibitory nature make it less favorite. Organosolv is not a cost-effective pretreatment process because of the high cost of catalysts, but it can be made cost-effective by recovering and recycling of solvents. Solvent removal is important because its presence effects fermentation, microorganism growth, and enzymatic hydrolysis. There is added risk of handling such harsh organic solvents. Acid helps in hydrolysis and depolymerization of lignin. Upon cooling lignin is dissolved in phenol, and in the aqueous phase, sugars are present. Formasolv involving formic acid, H2O, and hydrochloric acid is a type of organosolv in which lignin is soluble and at low temperature process can be carried out. For pretreatment with ethanosolv cellulose, hemicellulose and pure lignin can be recovered, but high pressure and temperatures are required when ethanosolv is used, and less toxic nature of ethanol as compared to other organosolv makes it favorite for pretreatment. Ethanosolv when used in pretreatment effects the enzymatic hydrolysis, so to prevent this low ethanol, water is used [62]. Recovery of ethanol and water reduces the overall cost of the pretreatment. For sugarcane bagasse Mesa et al. [63] used ethanosolv at 195°C for 60 min, and results showed formation of 29.1% sugars from 30% ethanol. Alcohol-based organosolv pretreatment is combined with ball milling by Hideno et al. [24] to pretreat Japanese cypress and observed a synergistic effect on digestibility. 50.1, 41.7, and 48.1% yield of organosolv pulping was obtained from ethylene glycol-water, acetic acid-water, and ethanol-water in a study done by Ichwan and Son [64]. Poplar wood chips were first treated with stream and then with organosolv to separate cellulose, lignin, and hemicellulose. About 88% hydrolysis of cellulose to glucose, 98% recovery of cellulose, and 66% increase in lignin extraction were reported by Panagiotopoulos et al. [65].
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3.4 Ionic liquids
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For the pretreatment of lignocellulose, scientist took a great interest in using ionic liquids, for decades. Ionic liquids containing cations or anions are a new class of solvents with high thermal stability and polarity, less melting point, and negligible vapor pressure [66, 67]. Normally large organic cations and small inorganic anions compose ionic liquids. Factors like degree of anion charge delocalization and cation structure significantly effect physical, biological, and chemical ionic liquid properties. Interactions between ionic liquids and biomass get affected by temperature, cations and anions, and time of pretreatment.
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Ionic liquids actually compete for hydrogen bonding with lignocellulosic components, and in this competition disruption of network occurs. 1-Ethyl-3-methylimidazolium diethyl phosphate-acetate, 1-butyl-3-methylimidazolium-acetate, cholinium amino acids, cholinium acetate, 1-ethyl-3-methylimidazolium diethyl phosphate-acetate, 1-allyl-3-methylimidazolium chloride, and chloride are ionic liquids used for the treatment of rice husk, water hyacinth, rice straw, kenaf powder, poplar wood, wheat straw, and pine. Among other ionic liquids are imidazolium salts which are most commonly used [42]. 1-Butyl-3-methylimidazolium chloride is used for pretreatment by Dadi et al. [68] who observed a twofold increase in yield and rate of hydrolysis. For the pretreatment of rice straw, Liu and Chen [69] used 1-butyl-3-methylimidazolium chloride also known as (Bmim-Cl) and observed significant enhancement in the process of hydrolysis due to modifications in the structure of wheat straw by Bmim-Cl. Bmim-Cl played role in the reduction of polymerization and crystallinity. A twofold increase in hydrolysis yield from sugarcane bagasse was observed in a study by Kuo and Lee [70] as compared to untreated bagasse. 1-Ethyl-3-methylimidazolium-acetate is used in a study by Li et al. [71] for the pretreatment of switch grass in order to remove lignin at a temperature of 160°C for 3 hours. Results showed 62.9% lignin removal enhanced enzymatic digestibility, and reduced cellulose crystallinity was reported by Tan et al. [72] on palm tree pretreatment with 1-butyl-3-methylimidazolium chloride. Slight changes in composition of biomass occurred after ionic liquid pretreatments although significant changes were observed in the structure of biomass. Ionic liquid pretreatment is less preferred over other techniques because of high thermal and chemical stability, less dangerous conditions for processing, low vapor pressure of solvents, and retaining liquid state at wide range of temperature. Ionic liquids can be recycled easily and are non-derivatizing. Disadvantage of using ionic liquid pretreatment is that noncompatibility of cellulase and ionic liquids results in the unfolding and inactivation of cellulase. At less viscosity cellulose solubilizes at low temperature; that’s why while using ionic liquids, viscosity is an important factor to be considered regarding the energy consumption of the whole process. High temperatures trigger more side reactions and negative side effects like reducing ionic liquid stability [73].
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3.5 Ozonolysis
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Ozone pretreatment is a great option for lignin content reduction in lignocellulosic biomass. In vitro digestibility of biomass is enhanced by the application of ozone pretreatment. Inhibitors are not formed in this pretreatment which is a great advantage because other chemical pretreatments produce toxic residues. In ozone pretreatment, ozone acts as an oxidant in order to break down lignin. Ozone gas is soluble in water and being a powerful oxidant, by breaking down lignin, releases less molecular weight, soluble compounds. Wheat straw, bagasse, cotton straw, green hay, poplar sawdust, peanut, and pine can be pretreated with ozone in order to degrade lignin and hemicellulose; however, only slight changes occur in hemicellulose, whereas almost no changes occur in cellulose. Ozonolysis apparatus consists of ozone catalytic destroyer, iodine trap used for testing efficiency of catalyst, oxygen cylinder, ozone generator, three-way valve, ozone UV spectrophotometer, pressure regulation valve, process gas humidifier, vent, and automatic gas flow control valve [40, 41, 74, 75, 76]. Moisture content hugely effects oxidization of lignin via ozone pretreatment as lignin oxidation decreases with increase in the moisture content of biomass. Ozone mass transfer is limited at less water concentration, which ultimately effects its reactivity with biomass. Longer residence time of ozone is caused by the blockage of pores by water film [77]. During ozonolysis, pH of water decreases because of the formation of organic acids. Alkaline media trigger delignification because it removes lignins that are bonded to carbohydrates [78, 79].
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Biomass delignification is associated with the production of inhibitory compounds. Certain aromatic and polyaromatic compounds are produced as a result of delignification [80]. Structural changes in lignin are observed by Bule et al. [81] in a study; different lignin subunits showed aromatic opening and degradation of β-O-4 moieties in NMR analysis. How do aromatic structures of control- and ozone-pretreated samples differ? A spectrum showed a decrease in aromatic carbon signal concentration. Changes were observed in methoxy groups that suggest the breakdown of ester-linked structure. Different reactor designs are used for the ozone pretreatment of biomass, for example, batch reactor, Drechsel trap reactor, fixed bed reactor, rotatory bed reactor, and multilayer fixed bed reactor. Plug flow reactors are used by most researchers [82]. Heiske et al. [83] compared the characteristics of single layered and multiple layered bed reactors in order to improve the wheat straw conversion to methane. Straw with 16.2% lignin concentration was obtained from single layered reactor, whereas in multiple layered reactor, lignin concentration decreased up to 7.2% at the bottom layer. Due to wax degradation in ozone-pretreated wheat straw, production of fatty acid compounds is observed by Kádár et al. [84]. About 49% lignin degradation was observed when corn stover was pretreated with ozonolysis in a study by Williams [85].
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4. Physicochemical pretreatment
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4.1 Ammonia fiber expansion (AFEX)
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AFEX technique belongs to the category of physicochemical pretreatment methods. In this low temperature process, concentrated ammonia (0.3–2 kg ammonia/kg of dry weight) is used as a catalyst. Ammonia is added to biomass in a reactor of high pressure; after 5–45 min of cooking, pressure is released rapidly. Normally temperature around 90°C is used in this process. Ammonia can be recovered and reused because of its volatility. The principle of AFEX is similar to steam explosion. Apparatus for AFEX includes reactor, thermocouple well, pressure gauge, pressure relief valve, needle valve, sample cylinder, temperature monitor, and vent. Rate of fermentation is seen to be improved by AFEX pretreatment of various grasses and herbaceous crops. For treatment of alfalfa, wheat chaff and wheat straw AFEX technology is used. Hemicellulose and lignin cannot be removed by using AFEX technology; hence, small amount of material is solubilized only. Degradation of hemicellulose into oligomeric sugars and deacetylation occur during AFEX pretreatment which is the reason of hemicellulose insolubility. After AFEX pretreatment of Bermuda grass and bagasse, 90% hydrolysis of cellulose and hemicellulose was achieved. Effectiveness of AFEX pretreatment decreases with increase in the lignin content of biomass, for example, newspaper, woods, nutshells, and aspen chips. In case of AFEX pretreatment for newspaper and aspen chips, maximum hydrolysis yield was 40% and 50%, respectively. So for the treatment of biomass with high lignin content, AFEX pretreatment is not a suitable choice.
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Ammonia recycle percolation (ARP) is another method that uses ammonia. Aqueous ammonia (10–15 wt %) is used in this method. With a fluid velocity of 1 cm/min and temperature of 150–170°C and residence time of 14 minutes, aqueous ammonia passes through biomass in this pretreatment, and ammonia is recovered afterwards. Under these conditions, ammonia reacts with lignin and causes the breakdown of lignin breakdown linkages. Liquid ammonia is used in AFEX technique whereas in ammonia recycle percolation method/technique, aqueous ammonia is used.
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4.2 Steam explosion
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In this method, high-pressure saturated steam is used to treat lignocellulosic biomass, and then suddenly pressure is reduced, due to which lignocellulosic biomass undergoes explosive decompression. Initiation temperature of steam explosion 160–260°C and 0.69–4.83 MPa pressure is provided for few seconds to minutes, and then lignocellulosic biomass is exposed and retained at atmospheric pressure for a period of time; this triggers hydrolysis of hemicellulose and at the end explosive decompression, terminated the whole process. Cellulose hydrolysis potential increases due to the cellulose degradation and lignin transformation caused by high temperature. During the steam explosion pretreatment, acid and other acids formed, which played their role in the hydrolysis of hemicellulose. Fragmentation of lignocellulosic material occurs due to turbulent material flow and rapid flashing of material to atmospheric pressure [86, 87, 88]. In steam explosion pretreatment, the use of sulfuric acid or carbon dioxide decreases time, temperature, and formation of inhibitory products and increases hydrolysis efficiency that ultimately leads to complete removal of hemicellulose. Steam explosion pretreatment is not that effective for pretreating soft woods; however, acid catalyst addition during the process is a prerequisite to make the substrate accessible to hydrolytic enzymes. By using steam, targeted temperature can be achieved to process the biomass without the need of excessive dilution. Sudden release of pressure quenches the whole process at the end and also lowers the temperature. Particulate structure of biomass gets opened by rapid thermal expansion which is used to terminate the reaction. Steam explosion gets affected by certain factors like moisture content, residence time, chip size, and temperature. By two ways optimal hydrolysis and solubilization of hemicellulose can be achieved; either use high temperature and short residence time or low temperature and high residence time. Low energy requirement is a great advantage of steam explosion pretreatment, whereas in mechanical pretreatment 70% more energy is required as compared to steam explosion pretreatment in order to obtain the same, reduced particle size. So far steam explosion pretreatment with addition of a catalyst is tested and came closest to scaling up at commercial level due to its cost-effectiveness. In Canada, at Iogen demonstration plant, steam explosion pretreatment is used at a pilot scale. For hardwood and agriculture residues, steam explosion pretreatment is a very effective pretreatment process.
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4.3 Carbon dioxide explosion
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Supercritical carbon dioxide explosion treatment falls in the category of physiochemical pretreatment. Scientists had tried to develop a process cheaper than ammonia fiber explosion and a process which would operate at temperature lower than stream explosion temperature. In this process, supercritical carbon dioxide is used that behaves like a solvent. Supercritical fluids are compressed at room temperature above its critical point. When carbon dioxide is dissolved in water, carbonic acid is formed which causes less corrosiveness due to its special features. During the process, carbon dioxide molecules enter into small pores of lignocellulosic biomass due to its small size. Carbon dioxide pretreatment is operated at low temperature which helped in prevention of sugar decomposition by acid. Cellulosic structure is disrupted when carbon dioxide pressure is released which ultimately increased the accessibility of the substrate to the cellulolytic enzymes for the process of hydrolysis [11, 40, 41, 43]. Dale and Moreira [89] used carbon dioxide pretreatment for alfalfa and observed 75% theoretical release of glucose. Zheng et al. [90] performed experiments to show comparison among ammonia explosion, steam pretreatment, and carbon dioxide pretreatment of recycled paper and sugarcane bagasse. The results showed that carbon dioxide explosion pretreatment is cost-effective than AFEX.
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4.4 Liquid hot water (LHW)
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Hot compressed water is another terminology used for this method of treatment. High temperature (160–220°C) and pressure (up to 5 MPa) are used in this type of pretreatment in order to maintain the liquid state of water. However, chemicals and catalysts are not used in liquid hot water pretreatment method [42]. In this method, water in liquid form remains in contact with lignocellulosic biomass for about 15 min. In this treatment pressure is used to prevent its evaporation, and sudden decompression or expansion in this pretreatment process is not needed. This method has proved to be very effective on sugarcane bagasse, wheat and rye straw, corncobs, and corn stover. Different terms like solvolysis, aqueous fractionation, aquasolv, and hydrothermolysis are used by different researchers to describe this pretreatment method [42, 60, 91]. Based on biomass flow direction and water flow direction into reactor, liquid hot water pretreatment can be performed in three different ways. The first method is co-current pretreatment, which is carried out by heating biomass slurry and water at high temperature, holding it for a controlled residence time at pretreatment conditions, and finally applying cool environment. The second method involves the countercurrent pretreatment that engages pumping of hot water against biomass at controlled conditions. The third method is the flow-through pretreatment, which can be carried out by the flow of hot water through lignocellulosic biomass which acts like a stationary bed.
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To investigate the effect of liquid hot water pretreatment, a study was conducted by Abdullah et al. [92] that determined the different hydrolysis rates of cellulose and hemicellulose. Two steps of optimization of various conditions were considered. The first step was performed at less severity for hydrolyzing hemicellulose, whereas the second step was performed at high severity for cellulose depolymerization. Disadvantage of liquid hot water pretreatment is high energy consumption requirement for downstream process because of the involvement of large amount of water. However, the advantage of this process is that chemicals and catalysts are not required and no inhibitor is formed [60].
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4.5 Wet oxidation
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In this pretreatment method, oxygen/air and water or hydrogen peroxide is used to treat biomass at high temperatures (>120°C) for half an hour at 0.5–2 MPa pressure [11, 93]. This pretreatment method is also used for the treatment of waste water and soil remediation. This method has proven to be very effective for pretreatment of lignin enriched biomass. Certain factors like reaction time, oxygen pressure, and temperature effect the efficiency of wet oxidation pretreatment process. Water acts like acid at high temperature, so it induces hydrolysis reaction as hydrogen ion concentration increases with increase in temperature which ultimately decreases the pH value. Pentose monomers are formed as a result of hemicellulose breakdown in wet oxidation pretreatment, and oxidation of lignin occurs, but cellulose remains least affected. There are certain reports on the addition of alkaline peroxide or sodium carbonate. The addition of these chemical agents help in bringing down temperature reaction and reduce the formation of inhibitory compounds. Efforts to improve the degradation of hemicellulose at high temperature lead to the formation of inhibitory compounds like furfural and furfuraldehydes. However, amount of the production of inhibitors in wet oxidation pretreatment is certainly less than that of liquid hot water pretreatment or steam explosion method. There is extremely less possibility of using this process at industrial scale because of two reasons. One is the combustible nature of oxygen, and the other is the high cost of hydrogen peroxide used in the process [94].
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4.6 SPORL treatment
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SPORL stands for sulfite pretreatment to overcome recalcitrance of lignocellulose, and this technique is used for pretreatment of lignocellulosic biomass [95]. SPORL is performed in two steps. The first step involves treatment of biomass with magnesium or calcium sulfite for the removal of lignin and hemicellulose fractions. The second step involves the reduction in size of pretreated biomass via mechanical disk miler. Effect of SPORL pretreatment was studied by Zhu et al. [22, 23] on spruce chips by employing conditions like temperature 180°C, half an hour time duration, 8–10% bisulfite, and 1.8–3.7% sulfuric acid. By employing these conditions, more than 90% substrate was converted to cellulose when cellulase of 14.6 FPU and 22.5 CBU β-glucosidase was used in hydrolysis. Low-yield inhibitors like hydroxymethyl furfural (HMF) (0.5%) and furfural (0.1%) were produced during this process. These percentages are far less as compared to acid-catalyzed steam pretreatment of spruce. In another study, SPORL-pretreated Popular NE222, beetle-killed lodgepole pine, and Douglas fir were purified. Low contents of sulfur and molecular mass were obtained with high phenolic derivative production [96].
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SPORL pretreatment on switch grass with temperature ranging between 163 and 197°C, 3–37 min time duration, 0.8–4.2% sulfuric acid dose, and 0.6–7.4% sodium sulfite dose was performed by Zhang et al. [97]. The results with enhanced digestibility by the removal of hemicellulose due to sulfonation and decreased hydrophobicity of lignin were obtained. SPORL yielded 77.3% substrate as compared to 68.1% for dilute acid treatment and 66.6% through alkali pretreatment. When sodium sulfite, sodium hydroxide, and sodium sulfide were used in SPORL pretreatment of switch grass, an improved digestibility of switch grass was achieved. When SPORL treatment was applied with optimized conditions, 97% lignin and 93% hemicellulose were removed from water hyacinth, and 90% hemicellulose and 75% lignin were achieved for rice husk [98].
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5. Biological pretreatment
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Conventional methods for chemical and physical pretreatments require expensive reagents, equipment, and high energy. On the other hand, biological pretreatment requires live microorganisms for the treatment of lignocellulosic material, and this method is more environment friendly and consumes less energy. There are certain microorganism present in nature that exhibit cellulolytic and hemicellulolytic abilities. White-rot, soft-rot, and brown fungi are known for lignin and hemicellulose removal with a very little effect on cellulose. White rot is able to degrade lignin due to the presence of lignin degrading enzymes like peroxidases and laccases. Carbon and nitrogen sources are involved in the regulation of these degrading enzymes [41]. Cellulose is commonly attacked by brown rot, whereas white and soft rot target both lignin and cellulose contents of plant biomass. Commonly used white-rot fungi species are Pleurotus ostreatus, Ceriporiopsis subvermispora, Ceriporia lacerata, Pycnoporus cinnabarinus, Cyathus cinnabarinus, and Phanerochaete chrysosporium. Basidiomycetes species including Bjerkandera adusta, Ganoderma resinaceum, Trametes versicolor, Fomes fomentarius, Irpex lacteus, Lepista nuda, and Phanerochaete chrysosporium are also tested, and these species showed high efficiency for delignification [41, 99].
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Pretreatment of wheat straw was studied by Hatakka [100]. The results showed 13% conversion of wheat straw into sugars by Pleurotus ostreatus in duration of 5 weeks, whereas Phanerochaete sordida and Pycnoporus cinnabarinus showed almost the same conversion rate but in less time. For degradation of lignin in woodchips and to prevent cellulose loss, cellulase-less mutant of fungus Sporotrichum pulverulentum was developed [101]. Delignification of Bermuda grass by white-rot fungi Ceriporiopsis subvermispora and Cyathus stercoreus was studied that resulted in 29–32 and 63–77% improvement in delignification [102]. During the secondary metabolism in fungus P. chrysosporium, two lignin degrading enzymes, lignin peroxidase and manganese-dependent peroxidase, are produced in response to carbon and nitrogen limitation. Extracellular filtrates of various white-rot fungi contain these two enzymes.
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\n\n',keywords:"pretreatment methods, lignocellulosic biomass, biofuel production",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/67131.pdf",chapterXML:"https://mts.intechopen.com/source/xml/67131.xml",downloadPdfUrl:"/chapter/pdf-download/67131",previewPdfUrl:"/chapter/pdf-preview/67131",totalDownloads:947,totalViews:0,totalCrossrefCites:3,dateSubmitted:"September 10th 2018",dateReviewed:"February 6th 2019",datePrePublished:"November 18th 2019",datePublished:null,dateFinished:null,readingETA:"0",abstract:"Lignocellulosic biomasses are carbon neutral and abundantly available renewable bioresource material available on earth. However, the main problem that hinders its frequent use is the tight bonding within its constituents that include cellulose, hemicellulose, and lignin. The selection of pretreatment process depends exclusively on the application. Various pretreatment processes are primarily developed and utilized in effective separation of these interlinked components to take maximum benefit from the constitutes of the lignocellulosic biomasses especially for the production of biofuel. The major pretreatment methods include physical, chemical, thermophysical, thermochemical, and biological approaches. Various aspects of these different pretreatment approaches are discussed in this chapter.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/67131",risUrl:"/chapter/ris/67131",signatures:"Muhammad Nauman Aftab, Irfana Iqbal, Fatima Riaz, Ahmet Karadag and Meisam Tabatabaei",book:{id:"7608",title:"Biomass for Bioenergy",subtitle:"Recent Trends and Future Challenges",fullTitle:"Biomass for Bioenergy - Recent Trends and Future Challenges",slug:"biomass-for-bioenergy-recent-trends-and-future-challenges",publishedDate:"December 18th 2019",bookSignature:"Abd El-Fatah Abomohra",coverURL:"https://cdn.intechopen.com/books/images_new/7608.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"186114",title:"Dr.",name:"Abd El-Fatah",middleName:null,surname:"Abomohra",slug:"abd-el-fatah-abomohra",fullName:"Abd El-Fatah Abomohra"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Physical methods",level:"1"},{id:"sec_2_2",title:"2.1 Milling",level:"2"},{id:"sec_3_2",title:"2.2 Microwave",level:"2"},{id:"sec_4_2",title:"2.3 Mechanical extrusion",level:"2"},{id:"sec_5_2",title:"2.4 Pyrolysism",level:"2"},{id:"sec_6_2",title:"2.5 Pulse electric field (PEF)",level:"2"},{id:"sec_8",title:"3. Chemical pretreatments",level:"1"},{id:"sec_8_2",title:"3.1 Acid pretreatment",level:"2"},{id:"sec_9_2",title:"3.2 Alkali pretreatment",level:"2"},{id:"sec_10_2",title:"3.3 Organosolv",level:"2"},{id:"sec_11_2",title:"3.4 Ionic liquids",level:"2"},{id:"sec_12_2",title:"3.5 Ozonolysis",level:"2"},{id:"sec_14",title:"4. Physicochemical pretreatment",level:"1"},{id:"sec_14_2",title:"4.1 Ammonia fiber expansion (AFEX)",level:"2"},{id:"sec_15_2",title:"4.2 Steam explosion",level:"2"},{id:"sec_16_2",title:"4.3 Carbon dioxide explosion",level:"2"},{id:"sec_17_2",title:"4.4 Liquid hot water (LHW)",level:"2"},{id:"sec_18_2",title:"4.5 Wet oxidation",level:"2"},{id:"sec_19_2",title:"4.6 SPORL treatment",level:"2"},{id:"sec_21",title:"5. Biological pretreatment",level:"1"}],chapterReferences:[{id:"B1",body:'Field CB, Behrenfeld MJ, Randerson JT, Falkowski P. Primary production of the biosphere: Integrating terrestrial and oceanic components. Science. 1998;281:237-240\n'},{id:"B2",body:'da Costa Sousa L, Chundawat SP, Balan V, Dale BE. “Cradle-to-grave” assessment of existing lignocellulose pretreatment technologies. Current Opinion in Biotechnology. 2009;20(3):339-347\n'},{id:"B3",body:'Himmel ME. Biomass recalcitrance: Engineering plants and enzymes for biofuels production. 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Downloaded from http://aem.asm.org/ on September 12, 2013 by Nagaoka University of T. Am Soc Microbiol.\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Muhammad Nauman Aftab",address:"nauman535@yahoo.com",affiliation:'
Institute of Industrial Biotechnology, Government College University, Pakistan
Agricultural Biotechnology Research Institute of Iran (ABRII), AREEO, Iran
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With a qualitative study, we explore how Smartphone apps and social network sites (SNSs) are being used by individuals who want to take care of their health. Findings suggest that individuals are taking advantage of digital technologies to improve their wellbeing in several manners: they use wearable devices to monitor their health and track their physical activity, keep in touch with doctors and health coaches using instant mobile messaging applications, and join virtual communities seeking for advice and support. Being a member of these communities provides certain advantages and rewards that motivate individuals to act on their good intentions toward their health. Given the high rates of adoption of digital technologies, specific social marketing campaigns can be designed to influence health behavior, including health promotion and interventions to help individuals achieve personal goals and improve the quality of their life.",signatures:"Alicia De la Pena and Bernardo Amezcua",authors:[{id:"196878",title:"Dr.",name:"Alicia",surname:"De La Pena",fullName:"Alicia De La Pena",slug:"alicia-de-la-pena",email:"mktgheraldo@yahoo.com.mx"},{id:"204774",title:"Dr.",name:"Bernardo",surname:"Amezcua",fullName:"Bernardo Amezcua",slug:"bernardo-amezcua",email:"ban@prodigy.net.mx"}],book:{title:"Advances in Health Management",slug:"advances-in-health-management",productType:{id:"1",title:"Edited Volume"}}},{title:"Marketing Strategies for the Social Good",slug:"marketing-strategies-for-the-social-good",abstract:"Social network sites (SNS) have proven to be a good environment to promote and sell goods and services, but marketing is more than creating commercial strategies. Social marketing strategies can also be used to promote behavioral change and help individuals transform their lives, achieve well-being, and adopt prosocial behaviors. In this chapter, we seek to analyze with a netnographic study, how SNS are being employed by nonprofits and nongovernment organizations (NGOs) to enable citizens and consumers to participate in different programs and activities that promote social transformation and well-being. A particular interest is to identify how organizations are using behavioral economic tactics to nudge individuals and motivate them to engage in prosocial actions. By providing an understanding on how SNS can provide an adequate environment for the design of social marketing strategies, we believe our work has practical implications both for academicians and marketers who want to contribute in the transformation of consumer behavior and the achievement of well-being and social change.",signatures:"Alicia De La Pena",authors:[{id:"196878",title:"Dr.",name:"Alicia",surname:"De La Pena",fullName:"Alicia De La Pena",slug:"alicia-de-la-pena",email:"mktgheraldo@yahoo.com.mx"}],book:{title:"Marketing",slug:"marketing",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"38977",title:"Prof.",name:"Muhiuddin",surname:"Haider",slug:"muhiuddin-haider",fullName:"Muhiuddin Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/38977/images/6387_n.jpg",biography:"Muhiuddin Haider, Ph.D., is a Clinical Professor in Global Health in the University of Maryland School of Public Health’s Institute for Applied Environmental Health. Since 2009, he has been teaching undergraduate courses under the Public Health Science and Global Health Scholars Programs, while also teaching graduate level courses in the Global Health Certificate Program offered through the University of Maryland School of Public Health. In addition to teaching, Dr. Haider is currently a co-investigator in Project HEAL: Health through Early Awareness and Learning, an intervention to increase cancer screening in African American faith-based communities in Prince Georges County, Maryland. He is also the Principal Investigator on a study to assess the US Public Health Service Commissioned Corps Officers’ value to public health.\n\nDr. Haider is a highly skilled public health professional who has managed and led diverse public health projects and research studies in more than a dozen countries worldwide over the past thirty years, on behalf of several international agencies and universities. He has assisted multi-sector initiatives to advance the delivery of quality health care services in the areas of Avian Influenza, HIV/AIDS, TB, RH/FP, Malaria, and has developed expertise in the areas of health communication, health promotion, health education, and social marketing. His research into strategies of behavior change, application of social marketing tools and communications capacity building has led to several acclaimed publications.\n\nHe has led major public health projects in several countries in Africa and Asia, for which he utilized technical skills to stimulate innovative and culturally sensitive approaches grounded in organizational and technical soundness. His recent research and programmatic work has focused on avian and pandemic influenza, for which he has contributed to creating and adapting IEC, BCC, and IPC training materials to establish and implement best practices within public health care systems and promote public-private partnerships. \n\nDr. Haider has worked collaboratively on numerous occasions with counterparts in the veterinary and agriculture sectors and has advanced the \\One World, One Health\\ framework through curriculum development, targeted coursework for public health students, and the development of a concept paper endorsed by the DOD Veterinary Service Activity, Princeton University based One Health Initiative Advocacy Group, Agricultural Research Service, DOA, and WHO. Dr. Haider has developed and conducted training sessions for Media/Health Reporting, with special focus on AI through DOS/VOA and IBB. Recently, Dr Haider was awarded a Fulbright Scholar Grant to assist the Ecuadorian Nutritional Program, Universidad De Saint Francisco in Quito.",institutionString:null,institution:{name:"University of Maryland, College Park",institutionURL:null,country:{name:"United States of America"}}},{id:"196819",title:"Prof.",name:"Aida Isabel",surname:"Tavares",slug:"aida-isabel-tavares",fullName:"Aida Isabel Tavares",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/196819/images/system/196819.jfif",biography:"Aida Isabel Tavares holds a Ph.D. in Economic Analysis awarded by the Autonoma University of Barcelona in 2008. \r\nShe has been dedicated to research in Applied Health Economics and she published several articles in international peer-reviewed journals. She has also published one book in public economics. Her research areas include health economics and policy, health systems, socioeconomic determinants of health, regulation in health markets and economics evaluation. Dr. Tavares has also been teaching at different universities, specifically several courses related to microeconomics, public economics, and health economics. Currently, she collaborates with the Centre of Studies and Research in Health of the University of Coimbra in Portugal and she an Assistant Professor in Lisbon School of Economics and Management - University of Lisbon.",institutionString:"ISEG - Lisbon School of Economics & Management, University of Lisbon",institution:null},{id:"197261",title:"Prof.",name:"Beata",surname:"Gavurova",slug:"beata-gavurova",fullName:"Beata Gavurova",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Technical University of Košice",institutionURL:null,country:{name:"Slovakia"}}},{id:"198049",title:"Mr.",name:"Mohd Idzwan",surname:"Mohd Salleh",slug:"mohd-idzwan-mohd-salleh",fullName:"Mohd Idzwan Mohd Salleh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Malaya",institutionURL:null,country:{name:"Malaysia"}}},{id:"198833",title:"Dr.",name:"Pietro",surname:"Iaquinta",slug:"pietro-iaquinta",fullName:"Pietro Iaquinta",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Calabria",institutionURL:null,country:{name:"Italy"}}},{id:"198853",title:"Dr.",name:"Justyna",surname:"Kujawska",slug:"justyna-kujawska",fullName:"Justyna Kujawska",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Gdańsk University of Technology",institutionURL:null,country:{name:"Poland"}}},{id:"201172",title:"Dr.",name:"Tatiana",surname:"Vagasova",slug:"tatiana-vagasova",fullName:"Tatiana Vagasova",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"204774",title:"Dr.",name:"Bernardo",surname:"Amezcua",slug:"bernardo-amezcua",fullName:"Bernardo Amezcua",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"205599",title:"Prof.",name:"Rosni",surname:"Abdullah",slug:"rosni-abdullah",fullName:"Rosni Abdullah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"205600",title:"Dr.",name:"Nasriah",surname:"Zakaria",slug:"nasriah-zakaria",fullName:"Nasriah Zakaria",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"advertising-policy",title:"Advertising Policy",intro:"
In line with the Principles of Transparency and Best Practice in Scholarly Publishing, below is a more detailed description of IntechOpen's Advertising Policy.
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1. IntechOpen partners with third-party companies to serve ads and/or collect certain information when you visit our website. These companies may collect non-personally identifiable information (not including your name, address, email address or telephone number) during your visit to IntechOpen's website.
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1. IntechOpen partners with third-party companies to serve ads and/or collect certain information when you visit our website. These companies may collect non-personally identifiable information (not including your name, address, email address or telephone number) during your visit to IntechOpen's website.
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2. All advertisements and commercially sponsored publications are independent from editorial decisions and are linked to reader behaviour.
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5. IntechOpen has blocked advertisement of harmful products or services.
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6. Advertisements and editorial content are clearly distinguishable.
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7. Editorial decisions will not be influenced by current or potential advertisers and will not be influenced by marketing decisions.
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8. Advertisers have no control or influence over the results of searches a user may conduct on the website by keyword or search topic.
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. 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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. 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He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). 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From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. 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