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",isbn:"978-1-83969-206-2",printIsbn:"978-1-83969-205-5",pdfIsbn:"978-1-83969-207-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"555c180ed3eefc77d38259cc57bd8dfe",bookSignature:"Dr. Svetlana P. Chapoval",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10324.jpg",keywords:"Th2 Response, Th2 Cytokines, Asthma Classification, Differences in Diagnostics, FDA-Approved Treatments, Occupational Asthma, Exercise-Provoked Asthma, Medication-Induced Asthma, Th2-Independent Asthma, Asthma and COPD, Future Perspectives, Asthma Research",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 26th 2020",dateEndSecondStepPublish:"December 22nd 2020",dateEndThirdStepPublish:"February 26th 2021",dateEndFourthStepPublish:"May 17th 2021",dateEndFifthStepPublish:"July 16th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Assistant Professor at the University of Maryland School of Medicine, well-recognized for her work on HLA Class II-restricted allergen T cell epitopes, VEGF-induced lung DC modifications, and her recent discoveries on neuroimmune semaphorins 4A and 4D contributions to allergic airway inflammation and to Treg cell phenotype and function. She has served and continues to serve as a reviewer for over 20 peer-reviewed scientific journals.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"70021",title:"Dr.",name:"Svetlana P.",middleName:null,surname:"Chapoval",slug:"svetlana-p.-chapoval",fullName:"Svetlana P. Chapoval",profilePictureURL:"https://mts.intechopen.com/storage/users/70021/images/system/70021.png",biography:"Dr. Svetlana Chapoval completed her medical training in 1985 at Russian State Medical University and PhD training in 1994 at Gamaleya Scientific Research Institute of Epidemiology and Microbiology. She then completed her postdoctoral fellowship in Immunology at Mayo Clinic in 2002. From 2002 to 2005 Dr. Chapoval was an Associate Research Scientists in the Department of Pulmonary and Critical Care Medicine at Yale University. She joined the Center for Vascular and Inflammatory Diseases and the Program in Oncology of the University of Maryland Marlene and Stewart Greenebaum Cancer Center at University of Maryland School of Medicine in 2006 as an Assistant Professor. Dr. Chapoval’s research is focused on cellular and molecular mechanisms of lung chronic inflammatory diseases, asthma in particular, and novel molecules for disease immunotherapy. She is well-recognized for her work on HLA Class II-restricted allergen T cell epitopes, VEGF-induced lung DC modifications, and her recent discoveries on neuroimmune semaphorins 4A and 4D contributions to allergic airway inflammation and to Treg cell phenotype and function. Dr. Chapoval has served and continue to serve as a reviewer for 20+ peer-reviewed scientific journals. In 2015, she completed a 4-year term as an Associate Editor for a renowned journal.",institutionString:"University of Maryland",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Maryland, Baltimore",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"280415",firstName:"Josip",lastName:"Knapic",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/280415/images/8050_n.jpg",email:"josip@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copy-editing and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"7248",title:"Dendritic Cells",subtitle:null,isOpenForSubmission:!1,hash:"ce3caba88847e8b12beb992e7a63e1dc",slug:"dendritic-cells",bookSignature:"Svetlana P. Chapoval",coverURL:"https://cdn.intechopen.com/books/images_new/7248.jpg",editedByType:"Edited by",editors:[{id:"70021",title:"Dr.",name:"Svetlana P.",surname:"Chapoval",slug:"svetlana-p.-chapoval",fullName:"Svetlana P. Chapoval"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"52857",title:"Oxidative Stress and Disease",doi:"10.5772/65366",slug:"oxidative-stress-and-disease",body:'\nThe generation of free radicals is a continuous physiological process, fulfilling relevant biological functions. The mechanisms of generation of free radicals occur mostly in the mitochondria, cell membranes and cytoplasm. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed as unavoidable by-products of metabolism. During the metabolic processes, these radicals act as mediators for the transfer of electrons in various biochemical reactions. Its production, in appropriate proportions, is possible to generate adenosine triphosphate (ATP) through the electron transport chain; fertilization of the ovum; activation of genes and participation of defense mechanisms during the infection process [1]. The continuous production of free radicals during the metabolic processes culminated in the development of antioxidant defense mechanisms (enzymes and substances such as glutathione, metallothionein, vitamin A, vitamin C and vitamin E). These are intended to limit the intracellular levels of these reactive species and control the occurrence of damage caused by them. However, excessive production can lead to oxidative damage. The structural modifications in the molecules of nucleic acids, proteins and lipids caused by increased concentration of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) lead to various metabolic changes that may contribute to the development of neurological diseases, cardiovascular diseases, cancer, among others [2].
\nThe installation process of oxidative stress arises from an imbalance between oxidants and antioxidants in favor of excessive generation of free radicals or removal speed thereof. This process leads to the oxidation of biomolecules with consequent loss of its biological functions and/or homeostatic imbalances, whose manifestation is the potential oxidative damage to cells and tissues. Accumulation of ROS/RNS can result in a number of deleterious effects such as lipid peroxidation, protein oxidation and DNA damage [3].
\nDNA and RNA are chemically unstable and vulnerable to hydrolysis, nonenzymatic methylation and oxidation, due to its susceptibility to endogenous and exogenous damage. The endogenous genotoxic agents are mainly produced by cellular metabolism and composed of ROS and RNS, estrogen metabolites and aldehydes produced by lipid peroxidation [4, 5].
\nThere are two major endogenous oxidants causing nucleic acids damage: hydroxyl radicals (HO•) and peroxynitrite (ONO2−). One major source of ROS is the mitochondrial respiration because up to 5% of oxygen undergoes single electron transfer and generates superoxide anion radical (O2−). The superoxide dismutase (SOD) converts O2− to hydrogen peroxide that should be reduced by catalase (CAT) or glutathione peroxidase (GPx), however when transition metals are present, it is reduced to hydroxyl radicals (HO•). These radicals have a high reactivity, so it must be generated close to DNA or RNA in order to oxidize them. The generation of peroxynitrite (ONO2−) occurs by the reaction of nitric oxide (NO) and superoxide, both produced simultaneously in macrophages. Although these specimens can directly oxidize the nucleic acids, there is a secondary synergic mechanism of RNS to break the oxidative balance: the RNS are able to inhibit the enzyme FAPY glycosylase, a DNA repair mechanism to oxidation [6].
\nOxidative stress can lead to different lesions in DNA, including direct modification of nucleotide bases, training sites apurinic/apyrimidinic, single strand break and much less frequently, breaking double strands. Considering all the bases of the nucleotides, guanine is most susceptible to oxidative changes because it has lower reduction potential and hydroxyl radicals interact with the imidazole ring of this nitrogenous base at positions C4, C5 and C8 [7].
\nThe most studied marker for DNA oxidation is 8-hydroxydeoxyguanosine, a product of guanosine oxidation by HO• [6, 8]. This product is able to pair with adenine, generating a GC/TA mutation upon replication [6]. It is also known that oxidative stress regulates DNA methylation, playing a role in epigenetics regulation. Epigenetics constitutes several mechanisms of controlling gene expression without changing DNA sequence, but responding fast and precisely to environmental changes. One of the most characterized methods of epigenetic regulation is DNA methylation. The methylation of DNA CpG islands is mediated by DNA methyltransferases (DNMTs), but when the ROS or RNS interacts with cytosine, it is chemically modified from 5-methylcytosine to 5-hydroxymethylcytosine, which prevents DNMT binding and alters methylation patterns [9].
\nFor RNA oxidation, the most relevant marker is the homologue 8-hydroxyguanosine. It has been made clear that RNA is more often oxidized than DNA, due to its cellular location closer to ROS and RNS occurrence. The major consequences of RNA oxidization are the breakage of the strand and ribosomal dysfunction, preventing correct protein production [8].
\nThe effects of oxidation in proteins can be observed in impaired protein folding, side-chain oxidation and backbone fragmentation, resulting in loss of function and stop a variety of biochemical processes. Among the amino acids, the cysteines and methionines are more easily oxidizable, but this reaction is reversible through disulfite reductases activity. However, the cysteine can also suffer irreversible oxidation reactions leading to the formation of S-carboxymethylcysteine and S-(2-Succinyl)cysteine, which implies the formation of fumarate and dicarbonyl groups covalently bound to cysteine residues. When the amino acids lysine, proline, arginine and threonine are oxidized, occurs the production of carbonyl derivatives, which are used as markers for oxidative stress. In the oxidation of aromatic amino acids, such as tyrosine, different products are formed due to interaction with ROS – dityrosine or RNS – 3-nitrotyrosine [8].
\nThese oxidized-modified proteins are usually recognized and degraded in the cells, but some of them can accumulate over time and lead to cellular dysfunction. A physiological example is the lipofuscin, a brown-yellow pigment that is a product of iron-catalyzed oxidation (polymerization) of proteins and lipids, as it is extremely resistant to proteolysis, it accumulates and it is used as an aging marker [10].
\nIn biological systems, lipid peroxidation occurs in two forms, one enzymatically, involving the participation of cyclooxygenase and lipoxygenase in the oxidation of fatty acids and other nonenzyme medium, involving transition metal, the reactive species oxygen, nitrogen and others [11]. Excess peroxidation results are very damaging to the cell, despite contribute to the inflammatory response, due to its importance in the cascade reaction from arachidonic acid to prostaglandin formation. The action of free radicals on lipids leads to the formation of lipid hydroperoxides and aldehydes, such as malondialdehyde, 4-hydroxynonenal and isoprostanes that contribute further to increased cellular toxicity and can be detected in biological samples to measure oxidative stress. Lipid peroxidation disrupts the normal structure and function of lipid bilayers surrounding both the cell itself and in the membranes of organelles. In particular, the lipid peroxidation can alter membrane permeability, transportation and fluidity [12]. The chronicity of the process in question has important implications for the etiologic process of many chronic diseases, including atherosclerosis, diabetes, obesity, neurodegenerative disorders and cancer [1].
\nThe antioxidant defense system has the primary objective to maintain the oxidative process within physiological limits and subject to regulation by preventing oxidative damage from spreading, culminating in systemic irreparable damage. The enzymatic defense system includes enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). These enzymes act through mechanisms of preventing and/or controlling the formation of free radicals and species nonradical, involved with the initiation of chain reactions that culminate in propagation and process amplification and, consequently, the occurrence of oxidative damage. CAT and GPx enzymes act with the same purpose, to prevent the hydrogen peroxide accumulation. Such integrated action is of great importance, since this reactive species through the reactions of Fenton and Haber-Weiss, with the participation of iron and copper metals, culminates in the generation of OH• radical against which there is no enzyme system defense [13, 14].
\nThe human organism is constantly exposed to a vast number of molecules that can lead to oxidative stress, such as drugs and alcohol. However, there is a conserved cellular component to oxidative stress response, which is constituted by over 100 genes responsible for detoxification and antioxidant protein production. The first line of the antioxidant defense to exogenous toxins includes the enzymes involved in phase I and II metabolism. The phase I metabolism is responsible for increased compound polarity through oxidation, reduction or hydrolysis reactions. The phase II metabolism, in the other hand, is responsible for facilitating the cellular export of those compounds; its reactions are mainly glucuronidation, acetylation and sulfation [15].
\nThe enzymes that compose the cytochrome P450 are the most responsible for oxidation of drugs, chemicals and various endogenous substrates, such as eicosanoids, cholesterol, vitamin D3 and arachidonic acid [16]. The P450 is a superfamily of heme-thiolated enzymes with over 2000 members [17]. In humans, 57 functional genes and 58 pseudogenes are grouped according to the sequence similarity in 18 families and 44 subfamilies. The CYP-enzymes that belong to the families 1, 2 and 3 are responsible for metabolizing up to 90% of the drugs, this phase I drug oxidation system is frequently redundant, but many drugs are metabolized to a clinical concentration by one or few CYPs only [18].
\nIn steroidogenic tissues (converts cholesterol into pregnenolone via the P450 side chain cleavage enzyme) there is a prevalence of CYP450 enzymes located in mitochondria and the electron transport system is very susceptible to oxidative stress. During the electron transport, a leakage of electron to the ultimate acceptor leads to their binding to oxygen, being considered a primary source of ROS, this may result in acceleration of ROS production in mitochondria. In this context, it is considered the effectiveness of electron transfer from NADPH to CYP enzymes for monooxygenation of substrates as a source of ROS because during the uncoupling reaction, without the presence of any substrates, the electron-transfer chain oxidizes NADPH and yields ROS. During CYP2E1 metabolism is frequently observed this kind of uncoupling reactions, thus this enzyme is strongly associated to ROS production and oxidative stress [16]. The enzyme CYP2E1 is associated with the metabolism of small molecules, and can be induced by ethanol, obesity, diabetes and polyunsaturated fatty acids; this induction is related to toxicity and oxidative stress. Another mechanism of CYP2E1 activation is the reduction of glutathione levels, upon acetaminophen administration, for example. Besides, this drug increases lipid peroxidation and protein carbonylation, enhancing the ROS production due to higher activity of CYP2E1 and being associated to hepatotoxicity mediated by MAP-kinase pathway [16, 19].
\nGlutathione S-transferase (GST) is a family of intracellular enzymes that prevent the action of endogenous and exogenous toxins on the cells. GSTs are multifunctional enzymes that participate in the phase II of the xenobiotic metabolism and catalyze the nucleophilic attack of the reduced form of glutathione (GSH) to potentially hazardous compounds. How are involved in the metabolism of many carcinogens, environmental pollutants and cancer-fighting drugs, it is therefore reasonable to assume that the lack of specific isoenzymes has a significant effect on the tolerance of an organism to carcinogens [20]. Human GSTs are categorized into cytosolic/nuclear, mitochondrial and microsomal. Based on their amino acid sequences and/or nucleotide substrate specificity and immunological properties, seven classes of cytosolic GSTs are described: Alpha, Mu, Pi, Sigma, Theta, Omega and Zeta. Microsomal GSTs are designated MAPEG (membrane-associated proteins in eicosanoid and glutathione metabolism) and the only mitochondrial GST confirmed in humans is GST-kappa, which is also present in peroxisomes. GSTs are normally found in biological medium as homo or heterodimers and these dimers have two active sites whose activities are independent. After combining with reduced glutathione (GSH), these enzymes have higher specificity for a second substrate (the electrophilic). GST enzymes participate in the metabolism of endogenous and exogenous compounds, for example, polycyclic aromatic hydrocarbons, phenylalanine and tyrosine amino acids, testosterone and progesterone. These enzymes target endogenous compounds, maybe derived from peroxidation of polyunsaturated fatty acids present in cell membranes and the activity of reactive oxygen species [21–23].
\nConclusive evidence suggests that oxidative stress is a major contributor to the pathophysiology of a variety of neurodegenerative diseases, including Alzheimer\'s, Parkinson\'s, Huntington’s, tardive dyskinesia (TD), epilepsy and acute diseases of the central nervous system, such as spinal cord injuries and/or brain traumatic. The human brain is vulnerable to oxidative stress due to many facts such as (i) metabolism of catecholamines; (ii) decrease in antioxidants; (iii) presence of transition metals; (iv) occurrence of brain trauma/injury; and also (v) the brain is a organ that proportionally requires more oxygen and (vi) expresses low levels of antioxidant enzymes, which contribute to formation of ROS. As a consequence of redox unbalance in brain, one of the most affected structures is the lipid membrane [24].
\nParkinson’s disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta of the brain, leading to rigidity or slowing movements and postural instability. Most of the cases of PD are idiopathic and some cases are genetic-related, but in general context, aging is a determinant factor. In both idiopathic and genetic cases of PD, the oxidative stress plays a critical role in pathogenesis, being a common underlying mechanism. There is an elevated level of oxidized lipids, proteins and DNA associated with decreased glutathione level in the brain of PD patients. This increased susceptibility to oxidative damage in the dopaminergic neurons is due to (i) the presence of ROS generating enzymes, such as tyrosine hydroxylase and monoamine oxidase and (ii) these neurons contain iron, a catalyser of Fenton reaction (Fe(II) + H2O2-> Fe(III) + OH• + OH−) that leads to superoxide radicals and hydrogen peroxide production [25].
\nA fact of Alzheimer’s disease is the dysregulation of iron and copper homeostasis and various evidence of oxidative stress, mainly RNA oxidation. Neurons usually do not store big amounts of iron, but with aging there is an accumulation of iron in the brain, especially in microglia, astrocytes and neurons from cortex and hippocampus. If iron levels increase much more than ferritin, an iron-storage protein, it becomes free to catalyze Fenton’s reaction [26].
\nThe tardive dyskinesia (TD) is an adverse effect of antipsychotic use, it affects up to 25% of schizophrenic patients. However, as the majority of patients do not develop TD, it is considered that genetics factors may define its occurrence but TD pathophysiology remains unclear. One of the strongest hypotheses suggests that it is caused by oxidative stress originated from neurotoxic free-radical production upon antipsychotic medication. This affirmation is supported by genetic polymorphisms evaluated in genes that encode a mitochondrial enzyme that prevents oxidative damage due to energetic metabolism (manganese superoxide dismutase) and a cytosolic flavoenzyme that prevents quinone reduction (NADPH quinone oxidoreductase), playing a role in antioxidant defense [27].
\nMetabolic syndrome is a term that designates a cluster of health problems often associated to modern life style, including obesity, insulin resistance, dyslipidemia, impaired glucose tolerance and high blood pressure. The metabolic syndrome is diagnosed when at least three of the following alterations are present: visceral obesity (waist circumference >102 cm in men or >88 cm in women); raised arterial blood pressure (>130/85 mm Hg); dysglycemia (fasting plasma glucose >100 mg dL); raised triglyceride concentrations (>150 mg dL) and low high-density lipoprotein (HDL) cholesterol (<40 mg dL in men or < 50 mg dL in women) [28].
\nThe oxidative stress is related to metabolic syndrome in several ways: (i) H2O2 promotes insulin signaling, being associated with increased insulin resistance; (ii) superoxide anion is generated by angiotensin stimulation of NADPH and angiotensin II/angiotensin II type I receptor (AT1R), which plays a critical role in blood pressure control; (iii) hyperglycaemia leads to overproduction of superoxide by mitochondrial electron transfer chain, activating oxidative stress; (iv) elevated low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) are correlated with oxidative stress and the dyslipidemia treatment with rosuvastatin is known to reduce oxidative stress through raise of antioxidant enzymes [28].
\nDue to oxidative DNA damage there is a direct correlation between diabetes and cancer. Diabetic patients present high levels of ROS because of elevated glucose, fatty acids and insulin blood levels; combined to lower antioxidative capacity derived from reduced glutathione synthesis. To support those findings, it has been proved that polymorphisms in peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1A) – a protein that regulates mitochondrial electron transport, leads to decontrolled redox activity [29].
\nAtherosclerosis is defined as an arterial disease characterized by fibrous and cholesterol rich plaques. Atherosclerosis progression causes blood flow obstruction, hemorrhage due to rupture and thrombosis leading to strokes or myocardial infarctions. Many risk factors are associated with atherosclerosis development, the most widely known are serum low-density lipoprotein (LDL) cholesterol, low serum high-density lipoprotein (HDL) cholesterol, diabetes, hypertension, smoking, aging and oxidative stress [30].
\nDuring LDL oxidation, a progressive process and very important for the beginning of the formation of atheromatous plaque, the cholesterol is target of oxidants, which generate a variety of oxysterols. On the other hand, lipid peroxidation products (MDA and 4-HNE) can react with histidine, cysteine or lysine residues of proteins, leading to formation of stable Michael adducts with a hemiacetal structure or to Schiff bases that undergo a rearrangement generating the Amadori products. These aldehydes can derivatize Lys residues of apoB, which decreases the number of positive charges and interferes on LDL binding to LDLR and scavenger receptors [31].
\nIn endothelial cells, besides stimulating the antioxidant defense (mainly by glutathione), Nrf2 (nuclear factor (erythroid-derived 2)-like 2) suppresses inflammation-associated expression of adhesion molecules and cytokines, which are associated with the early stage of atherogenesis [29]. NAD(P)H oxidases (NOXs) are major sources of ROS in the vasculature, producing superoxide from molecular oxygen using NAD(P)H as the electron donor and endothelial NO synthase (eNOS) produce NO which represents a key element in the vasoprotective function of the endothelium. However, pathological conditions associated with oxidative stress may become eNOS inefficient and promote the rapid inactivation of NO by excess superoxide [32].
\nThere is growing evidence that reversal of oxidative stress with antioxidants can reduce the degree of myocardial ischemic injury and heart dysfunction [33].
\nThe pathological effects of NO and O2− in virus infection are in clear contrast to their beneficial antimicrobial effects in bacterial and fungal infections. In virus infections, NO and ONOO−, which are primitive host-defense molecules, cause nonspecific oxidative damage in virus-infected tissue, leading to various pathological events. Virus-induced oxidative stress has been reported during HIV, influenza virus, HBV, hepatitis C virus, encephalomyocarditis virus (EMCV), respiratory syncytial virus (RSV), dengue virus (DENV) and others [34].
\nStudies including rotavirus-infected patients showed that viral infection stimulates NO production, decreases superoxide dismutase and glutathione peroxidase activities and increases inducible nitric oxide synthase (iNOS) mRNA and iNOS expression in murine ileum [35].
\nInfluenza virus is probably the best characterized pathogen modulating redox homeostasis. Influenza-induced ROS production has been associated with host immune and inflammatory responses, as well as modulation of viral replication. Oxygen radicals and their derivatives are recognized as principal mediators of influenza virus-induced lung injury [36].
\nWithin the Flaviviridae family, hepatitis C virus infection promotes oxidative stress and manipulates antioxidant systems, leading to liver damage and chronic disease. Elevated levels of reactive oxygen species (ROS) are considered as a major factor contributing to HCV-associated pathogenesis. HCV core protein is considered as a major regulator affecting the release of ROS from mitochondria. In this context, mitochondria play a crucial role for the production of ROS in HCV-infected cells. Several pathways are affected upon HCV infection to result in an induction of autophagy that interferes with various steps of the viral life cycle to promote a permanent viral infection. The assembly and release of viral particles are closely linked to the VLDL synthesis and occur via the secretory pathway. Elevated glucose production, enhanced fatty acid uptake or upregulation of genes involved in lipid and cholesterol synthesis may contribute to oxidative stress-induced insulin resistance linked to HCV infection [36].
\nInduction of iNOS and production of NO, accumulation of ROS and RNS, as well as perturbation of the reduced glutathione (GSH) content are all signatures of Dengue virus (DENV) infection in different human cells and animal models. DENV infection resulted in an intracellular accumulation of NAD(P)H oxidase (NOX2)-derived ROS in monocyte-derived dendritic cells (Mo-DCs). Alteration in the redox status of DENV-infected patients has been associated with increased inflammatory responses, cell death and correlated with different parameters associated with dengue disease [37].
\nThe HPV infection, although necessary, is not sufficient to cause cancer and several studies have been devoted to the search for concurrent carcinogenic factors. Among these cofactors, many evidence support the role of ROS. It is clear that viral infection induces ROS that in turn causes damage to all types of biological macromolecules. Two different types of cooperative mechanisms are presumed to occur between ROS and HPV: (i) the ROS genotoxic activity and the HPV-induced genomic instability concur independently to the generation of the molecular damage necessary for the emergence of neoplastic clones. This first mode is merely a particular form of cocarcinogenesis and (ii) ROS specifically interacts with one or more molecular stages of neoplastic initiation and/or progression induced by the HPV infection [38, 39].
\nTherefore, it seems reasonable to hypothesize that, while in most cases the cells react to HPV infection and can overcome the virus-induced ROS by activating apoptosis leading to termination of viral replication and lesion regression, in some of the infected cells a steady state balance between ROS generation and detoxification is established, partly due to viral-induced antioxidant response. Thus, infected cells can aberrantly proliferate, paving the way to neoplastic progression HPV, exploit host cell survival mechanisms, through modulation of redox homeostasis, increasing the activity of catalase, SOD among other, as an adaptive response to the high ROS conditions of preneoplastic lesions. Elevated GST and GSH provide the HPV hosting cell with improved oxidative damage detoxifying systems, but suppression of p53 and iNOS together with induction of vascular endothelial growth factor (VEGF) and resistance to ROS leads to the suppression of apoptosis and generates an oxidant fitting cell phenotype. Therefore, the tumor cell adapts their metabolism in order to support their growth and survival, creating a paradox of high ROS production in the presence of high antioxidant levels [38, 39].
\nMany signaling pathways that regulate the metabolism of ROS are also linked to tumorigenesis [40, 41]. However, ROS can also promote tumor formation by inducing DNA mutations and pro-oncogenic signaling pathways. The production of low level of ROS is required for homeostatic signaling events. It can be driven by NAD(P)H and NAD(P)H oxidase (NOX), leading to the increase of cell proliferation and survival through the posttranslational modification of kinases and phosphatases. At moderate levels, ROS induce the expression of stress-responsive genes such as HIF1A, which in turn trigger the expression of proteins providing prosurvival signals, such as the glucose transporter GLUT1 (also known as SLC2A1) and vascular endothelial growth factor (VEGF). At low and moderate levels ROS can act as signaling molecules that sustain cellular proliferation and differentiation and activate stress-responsive survival pathways, stimulating the phosphorylation of protein kinase C (PKC), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK)1/2, phosphoinositide 3-kinase/serine-threonine kinase (PI3K/Akt), protein kinase B (PKB) and JUN N-terminal kinase (JNK) [40, 42].
\nThe regulation of oxidative stress is an important factor not only for tumor development but also for the responses to anticancer therapies. As high ROS levels are harmful to cells, oxidative stress can have a tumor-suppressive effect. This imparts pressure on cancer cells to adapt by developing strong antioxidant mechanisms. But despite having an enhanced antioxidant system, cancer cells maintain higher ROS levels than normal cells. At high levels, ROS can cause damage to macromolecules, including DNA; induce the activation of protein kinase Cδ (PKCδ), triggering senescence; and/or cause permeabilization of the mitochondria, leading to the release of cytochrome c and apoptosis. ROS are also involved in the increased expression of antioxidant genes related to the activation of transcription factors such as the Nrf2, activator protein 1 (AP-1), nuclear factor kB (NF-kB) and p53 [40–42].
\n\nThe role of ROS in carcinogenic process can be either pro or anti oncogenic, and it can be summarized as follows: (i) regulating tumor development and signaling pathways for cell progression through ERK1/2 activation and ligand-independent RTK activation; (ii) regulating chronic inflammation for example through NF-kB activation; (iii) controlling tumor suppressor expression and cell cycle inhibitors; (iv) mediating angiogenesis by the release of vascular endothelial growth factor (VEGF) and angiopoietin; (v) favoring metastasis and tissue invasion due to metalloproteinase secretion; (vi) avoiding cellular death by activating SRC and PI3K/AKT pathway. Additionally, generating ROS is the mechanism of attack used by most of chemotherapies and radiotherapy [43, 44].
\nKeap1 (Kelch-like ECH-associated protein 1) sequesters Nrf2 (nuclear factor erythroid-derived 2) in the cytoplasm by binding to its aminoterminal regulatory domain. Keap1 is a sulfhydryl (S)-rich protein, and several cysteine residues mediate the Keap1–inducer interaction. When the interaction between Keap1 and Nrf2 disrupts, it allows Nrf2 to translocate to the nucleus. In the nucleus, Nrf2 controls several different antioxidant pathways by activating the expression of GSTs and other genes. This control is important to avoid cellular wear caused by oxidative stress, thus hindering the onset of various diseases.
The interindividual variation of the activity of antioxidant enzymes, for example, GST, considered by both environmental factors (e.g., diet and exposure to toxins such as cigarette) and genetic, is directly related to the etiology of cancer. Cytosolic GST present polymorphisms in humans and, this is probably the cause for differences in interindividual response to xenobiotics. The first studies in this area have addressed the correlation between GSTM1 null and/or GSTT1 null genotypes and a higher incidence of lung cancer, bladder, breast, colorectal head/neck. The discovery of allelic variants of GSTP1, encoding enzymes with reduced catalytic activity, led many researchers to examine the hypothesis that the combinations of polymorphisms of the Mu class, Pi and Theta of GST contribute to disorders with environmental factors [45, 46]. Studies with mice that exhibited a homozygous deletion of Nrf2 showed that Nrf2 is critical for inducing hepatic glutathione S-transferase (GST), NAD(P)H: quinone oxidoreductase (NQO1) and regulating levels of glutathione (Figure 1) [47].
\n\nBesides genetic variants of GST, changes in phase I enzyme activity as encoded by the cytochrome P450 family can also have implications for the metabolism of specific nitrosamines from the tobacco, alcohol and other carcinogenic substances [48].
\nThe GST enzymes are part of an integrated protection system, so it is important to note that the efficiency of this system depends on the combined action of other enzymes, such as γ-glutamylcysteine synthase γGluCysS) and glutathione synthase, in order to provide glutathione as well as carriers to facilitate the elimination of glutathione conjugates [21].
\n\nThe modulation of intracellular ROS levels is crucial for cellular homeostasis, and different ROS levels can induce different biological responses. It can occur due to the accumulation of intrinsic and/or environmental factors, such as hypoxia, enhanced cellular metabolic activity, mitochondrial dysfunction, increased activity of oxidases, lipoxygenases and cyclooxygenases. The accumulation of free radicals can lead to important changes in the structure of nucleic acids, proteins and lipids, altering their functions with consequent impact on cellular metabolism. These changes create conditions favorable to the onset of different diseases. The determination of oxidative stress markers and plasma antioxidants can suggest a targeted therapy against deficiencies in cell protection systems and it could be useful in an attempt to minimize complications caused by increased oxidative stress, leading to a better prognosis of various diseases.
\nIn 1980, Furchgott noted that the endothelium produces and releases a vasodilatory substance named endothelium-derived relaxing factor (EDRF), which diffuses into adjacent vascular smooth muscle cells and results in vascular relaxation [1]. In 1987, EDRF was identified as nitric oxide (NO) by Ignarro [2] and Moncada [3]. Murad reported the vasodilatory effect of nitroglycerin and NO formation from nitroglycerin in 1977 [4]. However, at the time, it was not known that endogenous NO is produced and released as a physiological substance in the body, especially in the vascular endothelium.
High-temperature combustion accelerates the reaction of oxygen and nitrogen in air to generate nitrogen oxides (NOx), such as NO, NO2, and N2O3. A common source of NOx is car engines, among which diesel engines have particularly high production. NO reacts with O2 to produce NO2, which is more toxic than NO. Thus, NOx, including NO, is considered an air pollutant. Accordingly, measuring instruments and NO gas standards with known concentrations are needed to assess NO concentrations in air. In addition, NO gas has various industrial applications, including uses in the production of chemicals, semiconductors, integrated circuits, and memory storage elements and devices. Therefore, measuring instruments for NO and the delivery of NO from gas cylinders were developed long before the discovery of NO as a physiological substance in the body. NO is now recognized as a gas and a physiological substance. Pioneering clinicians determined that “as a gas, NO can be administered to the body through the lung.” It was fortunate for these clinicians who first conducted NO inhalation in humans that measuring instruments for NO and NO cylinders were available.
The present chapter discusses endogenous NO production in normal and hypertensive pulmonary vasculature, the history of NO inhalation for therapeutic use, the fate of inhaled NO (iNO), effects of iNO in remote organs other than the lung, and iNO as a therapeutic strategy in pediatrics.
NO is primarily synthesized by endothelial NO synthase (eNOS, NOSIII) in pulmonary vascular endothelial cells. NO reacts with a receptor, soluble guanylate cyclase (sGC), in adjacent smooth muscle cells. Activated sGC produces cGMP, which stimulates protein kinase G (PKG) and exerts many physiological effects, including pulmonary vascular relaxation. The inhibition of NO production by
The effects of NO differ among cell types. NO induces relaxation in vascular smooth muscle cells, prevents aggregation and adhesion in platelets, prevents adhesion in leucocytes, and acts as a neurotransmitter in synapses. Thus, NO regulates various cell functions. In the vasculature, NO is released from endothelial cells, reaches adjacent smooth muscle cells, and causes vascular relaxation, indicating that it functions in intercellular signaling. Among the physiological roles of endogenous NO, vascular relaxation was discovered first.
In isolated rat main pulmonary arterial rings precontracted with prostaglandin F2α (PGF2a), acetylcholine (ACh) induces relaxation in endothelium-preserved pulmonary arteries, but not in endothelium-denuded pulmonary arteries, suggesting that the endothelium in pulmonary arteries produces a relaxation-inducing substance in response to acetylcholine (Figure 1(a) and (b)).
(a) Acetylcholine induces relaxation in endothelium-preserved pulmonary arterial rings. Pulmonary artery rings were obtained from normal control air rats. Rings were suspended in an 20 ml organ bath, and isometric tension was measured. Relaxation responses to acetylcholine (Ach) in endothelium-preserved (END+) and endothelium-denuded (END-) rings of the extrapulmonary artery were obtained. Endothelium was removed by gently rubbing luminal surface by fine stainless wire in endothelium-denuded rings. Rings were precontracted with prostaglandin F2a (PGF2a). Relaxation induced by 10−4 M papaverine (Pap 4) was taken as 100%. Bars mean standard error. Relaxation responses to ACh were abolished in the endothelium-denuded pulmonary arterial rings, showing that pulmonary vascular endothelium releases vasorelaxation substance named endothelium-derived relaxing factor (EDRF). The absence of the endothelium was confirmed by scanning electron micrography (b). END−, endothelium-denuded rings; END+, endothelium-preserved rings; 8, 10−8 mol/L, the same for 7, 6, 5, and 4. (B) Scanning electron micrograph of the endothelium-preserved pulmonary artery and endothelium-denuded pulmonary artery. Endothelium was removed by gently rubbing luminal surface by fine stainless wire. Left: luminal surface of the endothelium-preserved pulmonary artery. Right: luminal surface of the endothelium-denuded pulmonary artery.
In pulmonary arteries isolated from experimental PH models (chronic hypoxic PH in rat), the relaxation response to acetylcholine (ACh) is depressed, as observed in endothelium-denuded arteries, suggesting that endothelial function is impaired in PH arteries. Both ACh- and sodium nitroprusside (SNP, an NO donor)-induced relaxations were impaired in pulmonary arteries from rats with chronic hypoxic PH, suggesting that NO-induced relaxation is depressed in hypertensive pulmonary arteries [7, 8] (Figure 2). However, the magnitude of impairment seems to be higher in ACh-induced endothelium-dependent relaxation than in SNP-induced endothelium-independent relaxation [7].
The relaxation responses are depressed in isolated pulmonary arterial rings from chronic hypoxic pulmonary hypertensive rat. Pulmonary artery rings were obtained from normal control air rats and rats exposed to 10 days of hypoxia with chronic hypoxic pulmonary hypertension (PH). Isometric tension was measured. Relaxation responses to acetylcholine (ACh) in prostaglandin F2a (PGF2a)-precontracted rings of extrapulmonary were recorded. Relaxation induced by 10−4 M papaverine (Pap 4) was taken as 100%. Relaxation responses to ACh were depressed in rings from rats with chronic hypoxic PH, showing that the release of vasorelaxation substance is impaired in PH rings. Although the relaxation responses to sodium nitroprusside (SNP) are impaired in pH rings compared with control, this means that there was a room where SNP could cause relaxation in PH rings from chronic hypoxic PH.
The relaxation responses to SNP are caused by the liberation of NO from SNP. To determine the vasodilatory effects of NO directly, a NO solution was made by bubbling 10% NO in pure N2 into deoxygenated distilled water. Although depressed, the relaxation responses were indeed induced by NO in hypertensive pulmonary arteries [7] (Figure 3). Importantly, iNO exhibits selectivity, resulting in vasodilation in pulmonary arteries (Figure 4) when administered by inhalation through the trachea. The intravenous injection of NO donors simultaneously decreases both pulmonary and systemic arterial pressure.
NO solution (0.16–0.2 mM NO) caused the relaxation responses in isolated normal and pulmonary hypertensive arterial rings. Pulmonary artery rings were obtained from normal control air rats (A), rats exposed to 10 days of hypoxia with chronic hypoxic pulmonary hypertension (PH) (B), and rats after 28 days of recovery in room air from chronic hypoxia (C). NO solution was made by bubbling 10% NO through deoxygenated distilled water, which results in 0.16–0.2 mM concentration. Aliquots (0.5 ml) of this solution were applied to the organ bath. Papaverine (Pap) was introduced to obtain maximal relaxation. Relaxation responses to NO solution to prostaglandin F2a-precontracted rings were recorded. (A) NO-induced relaxation in pulmonary artery rings from normal rats. (B) Response to NO was depressed in pulmonary artery rings from chronic hypoxic rats. (C) The relaxation response returned to normal after 28 days of recovery from chronic hypoxic pulmonary hypertension. The result of (B) showed that NO could dilate hypertensive pulmonary vascular smooth muscles, although depressed compared to normal.
Inhaled NO as selective pulmonary vasodilator in pulmonary hypertensive rats. A pulmonary artery catheter was introduced via the right external jugular vein into the pulmonary artery by a closed chest technique. Pulmonary arterial pressure(PAP) was recorded with rat fully awake in a pulmonary hypertensive rat (19 days after the single injection of monocrotaline). About 20 ppm NO inhalation decreased PAP with no change of arterial pressure. When NO inhalation was discontinued, the PAP returned to baseline.
Although the role of the eNOS-derived NO-related pathway in pulmonary arterial hypertension (PAH) has been determined, its pathophysiology remains unclear. eNOS plays a key role in this pathway. Giaid et al. detected decreased eNOS protein expression in human lungs with PAH [9]. Additionally, exhaled NO has been found to be lower in patients with PAH than in controls [10]. Subsequent studies have reported increased eNOS protein expression in plexiform lesions in PAH [11] and increased eNOS activity in idiopathic PAH (IPAH) lungs, despite no change in NOS expression [12]. The membrane protein caveolin-1 (CAV1) is a crucial negative regulator of eNOS activity. The CAV1 expression is decreased in IPAH lungs, which might lead to persistent eNOS activation, the accumulation of dysfunctional (i.e., uncoupled) eNOS, the formation of peroxynitrite, and the impairment of PKG kinase activity via tyrosine nitration [12]. Increased eNOS activity and/or expression might not be associated with NO production in PAH.
Animal studies using a monocrotaline (MCT)-induced PAH rat model, which is characterized by pulmonary endothelial damage and perivascular inflammation in the early pathological stage, have shown decreased eNOS expression [13] and/or phosphorylated eNOS activity [14] as well as decreases in sGC and PKG. Vasodilation induced by ACh, an endothelium-dependent NO-related vasodilator, was also impaired. Another adult rat model of severe PAH with precapillary obliterative lesion (SU/Hx model) shows similarities in the pulmonary vascular pathology to that of PAH in adults. This SU/Hx model, induced by combined SUGEN5416 (a vascular endothelial growth factor receptor II antagonist) and exposure to chronic hypoxia, showed a reduction of ACh-induced NO production and/or release in pulmonary arteries [15]. Another recent study has reported decreased CAV1 expression in the same model [16]. eNOS also translocates from cell surface caveolae to cytoplasmic and perinuclear regions in pathological state [17]. Consequently, the amount of NO production is decreased. Accordingly, the pathogenesis and progression of PAH may be partially induced by endothelial dysfunction associated with suppression of the eNOS-NO-related pathway.
Genetic variants in the eNOS-NO-cGMP pathway might cause PAH. CAV1 plays an important role in NO signaling in PAH. Mutations in CAV1 have been identified in PAH [18]. The gene encoding bone morphogenetic protein receptor 2 (BMPRII) is frequently mutated in heritable PAH [19, 20] and adult IPAH [19, 21]. BMPRII is a member of the transforming growth factor (TGF)-β receptor superfamily, localized to caveolae, and interacts with CAV1 in vascular smooth muscle cells [22, 23]. Recent studies have demonstrated that BMPRII deficiency promotes SRC-dependent caveolar trafficking defects [24]. In addition, CAV1-deficient mice have shown reduced BMPRII expression after exposure to chronic hypoxia [16]. In MCT-treated pulmonary arterial endothelial cells, BMPRII was increasingly trapped intracellularly together with increased trapping CAV1 and eNOS. These results suggest that NO-cGMP-related dysfunction and BMPRII deficiency are closely related to and play a significant role in the pathogenesis of PAH.
Pulmonary veno-occlusive disease (PVOD), classified as a PAH subgroup, is inextricably associated with pulmonary capillary hemangiomatosis (PCH) [25]. Pulmonary vascular lesions in this condition are mainly detected in postcapillary venules and veins but are also found in pulmonary capillaries and arteries [25]. The pathogenesis is heterogeneous and poorly understood [25]. These are rare diseases, and few studies have focused on the pathogenesis and pathophysiology. Kradin et al. reported that eNOS expression in abnormal capillary lesions is significantly decreased in patients with PCH with pulmonary vascular remodeling and concomitant pulmonary hypertension and is minimally decreased or not decreased in patients without pulmonary vascular remodeling [26]. These results suggest that the alteration of eNOS expression is associated with the pathogenesis of these complicated conditions. Further experiments are necessary to determine the precise role of the eNOS-NO-cGMP pathway in PVOD/PCH.
Biallelic mutations in eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) have been identified in familial and idiopathic PVOD/PCH. EIF2AK4 encodes general control nonderepressible 2 (GCN2) [27]. The most common experimental models of these conditions are mitomycin C (MMC)-treated rats and mice [28]. Interestingly, MMC dose dependently induces pulmonary GCN2 depletion [28]. EIF2AK4 mutations are also found in sporadic PVOD/PCH [27]. Mutation carriers have distinct histological features, including strong muscular hyperplasia of the interlobular septal vein as well as arterial severe intimal fibrosis [29]. EIF2AK4 is activated by amino acid depletion. Because
The pathophysiologic features of lung diseases include chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) and mixed pathologic diseases, including combined pulmonary fibrosis and emphysema. All involve alveolar hypoxia and subsequent hypoxic pulmonary vasoconstriction. eNOS expression is upregulated in acute hypoxia in rat lungs [30]. eNOS expression increases in a time-dependent manner in rats during the development of hypoxia-induced PH [31, 32, 33], while eNOS activity is impaired [34]. The production of tetrahydrobiopterin (BH4), an obligatory cofactor for generating the active dimer form of eNOS, was altered in hypoxic conditions [34]. An imbalance between BH4 and dihydrobiopterin (BH2) may cause eNOS uncoupling and inactive monomer formation [34]. Several studies have reported decreased eNOS expression and/or activity in patients with COPD [35, 36], with severity of endothelial dysfunction correlated with degree of airflow obstruction [36]. eNOS is also absent in pulmonary arteries of patients with IPF [37]. As the histological features of this disease differ from those of COPD, the pathogenesis of IPF-induced PH may include a multifactorial and complex process involving proinflammatory cytokines and growth factors.
In 1988, at the international conference of the American Thoracic Society, Higenbottam presented his team’s paper titled “Inhaled endothelium-derived relaxing factor (EDRF) in primary pulmonary hypertension (PPH),” including the first description of NO inhalation in humans with pulmonary arterial hypertension for laboratory use [38]. In 1991, Lancet published the study [39], showing that 40 ppm NO inhalation selectively reduces PAP, with no changes in systemic pressure. Frostell et al. also showed that inhaled NO (5–80 ppm) causes selective pulmonary arterial dilatation, without changes in systemic arterial pressure in sheep [40], where PAP elevation was induced by hypoxic pulmonary vasoconstriction. Both research groups referenced the studies by Yoshida, Kasama, and Kitabatake about the metabolic fate of iNO [41, 42] because toxicity and retention in the human body should be minimal. NO has been a focus in air pollution research and thus provides a basis for work by clinicians evaluating NO inhalation in humans. In rats with chronic hypoxia- and MCT-induced PH, iNO results in a decrease in PAP with no changes in systemic arterial pressure [43, 44, 45] (Figure 4).
iNO dilates the pulmonary vasculature by NO combining with guanylate cyclase Fe in pulmonary vascular smooth muscle cells. Most NO diffuses into the blood at alveoli, where it reacts with the Fe of oxygenated hemoglobin (oxy-Hb, O2Hb, O2Hb(Fe2+)) in red blood cells and is converted to NO3−. When NO reacts with oxy-Hb Fe2+ or combines with the Fe2+ of deoxygenated Hb (deoxy-Hb, deoxy-Hb(Fe2+)) in red blood cells, iNO does not have direct vasodilatory effects because it reacts or combines with Hb Fe2+ and becomes unable to combine with guanylate cyclase Fe of smooth muscle cells in systemic arteries. Thus, iNO is a selective pulmonary vasodilator, causing decreased PAP with no changes in systemic pressure (Figure 4).
The clinical use of NO inhalation is aimed at inducing selective pulmonary arterial dilation and treating PH and right ventricular failure. NO inhalation is also used to test pulmonary vascular reactivity in catheterization labs, which will be discussed in the last section of this chapter. Improved arterial oxygenation is also expected in patients with high intrapulmonary shunting [46]. Thus, the main target of iNO is lung and pulmonary circulation. In addition, iNO effects on remote organs, such as the kidney [47], liver [48, 49], heart [50], and muscle [51], have been investigated, with iNO shown to ameliorate inflammation and ischemia-reperfusion injury.
NO reacts or combines with transition metal ions, such as thiols (–SH, –SS–, and HS–). Many enzymes and substances involved in regulating cell function include in their structure Fe, a transitional metal, thus suggesting its importance as an NO target. Because hemoglobin (Hb) and guanylate cyclase contain heme, which includes Fe in its structure, NO reacts or combines with Hb and guanylate cyclase. NO also combines with enzymes containing Fe–S in their structure, and combined NO (nitration) and Fe–S can prevent enzymatic activity. High concentrations of NO induce cell damage, which presumably result from this enzymatic dysfunction. Thus, NO is a double-edged sword. Although an appropriate amount is important for regulating cell function, an excess dysregulates cell function and causes damage.
RS–NO is a complex of SH– and NO. Nitrosothiol is a thionitrite including S-nitroso-albumin, where NO combines with cysteine, a component of albumin. –SH is a component of amino acids, peptides, and proteins. NO binds to –SH, forming S-nitrosothiol, 96% of which is S-nitrosoprotein. About 82% of S-nitrosoprotein is serum S-nitrosoalbumin. Thus, endogenous NO circulates in the form of S-nitrosoalbumin [52].
NO targets are transition metal ions, oxygen, nucleophilic centers (thiols, amides, carboxyls, and hydroxyls), and free radicals. iNO targets are (Figure 5) also transition metal ions, namely, in the guanylate cyclase Fe, Hb Fe, iron-sulfur (Fe-S) center. Other targets include oxygen (gaseous oxygen in the airway and alveoli), dissolved oxygen in the tissue and body fluids, the nucleophilic center of organic compounds (–S–S– and –SH), and free radicals (reactive oxygen species produced in leucocytes and macrophages). Among these substances that react with iNO, The main target of an approved medical iNO gas is guanylate cyclase Fe in pulmonary vascular smooth muscle cells.
The substances in the lung to react or combine with iNO. NO reacts with Fe in the guanylate cyclase (GC) and induces cyclic GMP and subsequent pulmonary vascular relaxation; NO reacts with Fe2+ in O2Hb and forms MetHb and NO3−; NO and Fe2+ in deoxy-Hb combine in NOHb; NO and O2 combine in NO2; NO and O2- combine in ONOO-; NO and OH- combine in NO2-; NO and thiol (sulfhydryl group, -SH group), amine, and iron-sulfur (Fe-S) center combine in nitrosothiol, nitrosamine, and Fe-S NO, respectively. RSH is a compound including SH group. S-nitro-Hb is combination of NO and SH in the cysteine in the Hb beta subunit. Reactive oxygen species (O2−, OH−) are produced in leucocytes and macrophages.
Oxidation refers to electron loss and reduction to electron gain. Reducing agents release electrons, whereas oxidizing agents receive electrons. The term redox is a combination of “reduction and oxidation reaction.” Reduction and oxygenation occur simultaneously so that when a reducing agent is oxidized, an oxidizing agent is also reduced. Nitrogen monoxides involve an array of species: NO+ (nitrosonium), NO·, and NO− (nitroxyl anion) [53]. Among these, NO· has a single electron, and its removal forms NO+, whereas its addition yields NO−. NO· is electrically neutral, which contributes to its free diffusibility in aqueous medium and across cell membranes.
The main NO· targets are oxygen and transition metal ions. The various redox forms of oxygen, such as superoxide (O2−) and (di)oxygen, are candidates in both the gas phase and aqueous solution. Metalloproteins, such as heme-containing protein and non-heme-containing protein, and iron-sulfur clusters also react with NO·.
iNO reacts with oxy-Hb. NO oxidizes oxy-Hb to form MetHb. In other words, MetHb is oxidized oxy-Hb. Oxidized iron (MetHb) species do not catch NO, and iNO during cardiopulmonary bypass (CPB) decreases acute kidney injury [47]:
NO reacts or combines with Hb in three ways: (1) NO combines with in the heme Fe to form NOHb (nitrosyl Hb), a metal nitrosyl species; (2) NO− combines with amines in Hb to form S-nitroso-Hb, a nitrosamine, where NO combines with cysteine in the beta subunit of Hb; and (3) O− or NO+ combines with the sulfhydryl center (-SH) in Hb. NO reacts with oxy-Hb and combines with deoxy-Hb. If NO reacts with oxy-Hb (Fe2+), MetHb (Fe3+) and nitrate (NO3−) are formed. If NO combines with deoxy-Hb (Fe2+), NOHb (Fe2+) is formed, after which NOHb (Fe2+) reacts with O2 to form MetHb (Fe3+) and NO3−. MetHb (Fe3+) is reduced to deoxy-Hb (Fe2+) by MetHb reductase. The depletion of MetHb reductase or high production of MetHb causes methemoglobinemia. NO3− is excreted in the urine (Figures 6, 7).
Reaction of NO with Hb. NO reacts with Fe2+ of oxy-Hb making MetHb and NO3− and combines with deoxy-Hb making NOHb. NOHb reacts with O2 making MetHb and NO3−.
In an in vitro experiment, Wennmalm [54] incubated NO with arterial and venous blood and measured MetHb, NOHb, NO3−, and NO2−. The reaction of NO with O2Hb was rapid in the arterial blood (oxygen saturation 94–99%). NOHb was low in arterial blood and high in venous blood (oxygen saturation 36–86%). These results suggest that O2Hb (oxy-Hb) gives O2 to NO making NO3−. In contrast, deoxy-Hb directly combines with NO making NOHb in the absence of oxy-Hb (i.e., in the presence of deoxy-Hb). The NO and oxy-Hb reaction is completed in 100 ms [55].
Nakajima and Oda have shown that the NOHb concentration is 0.13% in the blood during 20 min of 10 ppm NO inhalation [56]. This low concentration suggests the rapid turnover of NOHb, in which NOHb is presumably an intermediate in the conversion from NO to NO2− and NO3−.
When 5 mM NO2− is added to human blood, NO3− changes are detected within 10 min [57]. The intravenous injection of sodium nitrite to rabbits results in the rapid disappearance of NO2−. After the intratracheal injection of 13NO2−, 70% of 13NO2− changed to 13NO3−, and 26% remained as 13NO2− [58]. These observations suggest that NO2− is converted to NO3− in red blood cells [59]. NO2− and NO3− are stable and unchanged in plasma without red blood cells.
A clear understanding of the fate of iNO is critical for its clinical use in humans. As previously mentioned, the metabolic fate of iNO was examined in the early 1980s, and it was found that retention of iNO in the body was lacking (Figure 7).
Metabolic fate of NO. Almost all inhaled NO is converted to NO3−. Forty-five percent of NO3− is excreted in urine; 10% is changed to nitrogen compound except NO3− and NO2− and excreted in feces; 10% is changed to urea through the digestive tract and liver and excreted in urine. The rest will be changed to N2 in the stomach and discharged outside of the body.
An inhalation study of 15NO in rats investigated the metabolism of iNO. In the carcasses, 1.6% of total inhaled 15N was detected, similar to the level of natural 15N. This result suggests that iNO largely does not remain in the body. About 55% of total inhaled 15N was recovered in urine [41, 42], including 45% as nitrates and 10% as urea (Figure 7). About 10% of total inhaled 15N was recovered as undetermined nitrogen compounds in feces. The remaining 35% was not recovered but is assumed to be N2 produced from the reduction of NO3− → NO2− → N2 by stomach flora.
During cardiopulmonary bypass(CPB), hemolysis causes an increase in Hb plasma concentration due to the destruction of red blood cells. Hb includes oxy-Hb and deoxy-Hb. Oxy-Hb causes vasoconstriction, which is partly due to the depletion of NO available to induce vascular smooth muscle relaxation. NO is produced in and released from endothelial cells, some of which reaches adjacent vascular smooth muscles, causing vasorelaxation, and some of which diffuses into the plasma. If the amount of oxy-Hb in the plasma increases, the binding of NO to oxy-Hb increases, resulting in less NO reaching adjacent smooth muscle cells. Thus, the presence of large amounts of oxy-Hb might decrease NO availability in vascular smooth muscle cells (Figure 8).
NO formed in the endothelium is scavenged by plasma oxygenated Hb. (A) NO produced in the endothelium diffuses into adjacent smooth muscle cells and binds with guanylate cyclase. (B) If O2Hb (Fe2+) increases, NO produced in the endothelium diffuses into the blood and scavenged by O2Hb (Fe2+), decreasing the amount of NO diffused into smooth muscle cells. (C) If O2 Hb(Fe2+) is converted to MetHb(Fe3+) by NO inhalation, NO is not scavenged, which recovers the amount of NO diffusing to the smooth muscle side.
Acute kidney injury is a common complication after cardiac surgery with prolonged CPB. Because oxygen tension is high during CPB, plasma oxy-Hb exhibits substantial hemolysis, causing vasoconstriction in the kidney. Recently, NO was demonstrated to decrease the occurrence of acute kidney injury and chronic kidney disease 1 year postoperatively [47]. NO inhalation at 80 ppm was started at the onset of CPB via a CPB machine and was continued after CPB via a mechanical ventilator for 24 h or less if patients were ready to be extubated early. Under NO inhalation, oxy-Hb was converted to MetHb, which recovered NO availability to vascular smooth muscle cells due to the decrease in oxy-Hb. Thus, exogenous NO inhalation might increase endogenous NO availability to counteract renal vasoconstriction during CPB.
In brief, the reduction of nitrite and nitrate produces NO (Figure 9). Nitrite is reduced by deoxy-Hb, respiratory chain enzymes, xanthine oxidoreductase, deoxygenated myoglobin, and protons, facilitating the transfer of protons to NO2− and thereby producing NO. These reactions are intensified under acidic and hypoxic states. After iNO is converted to NO2− and NO3−, NO can be recycled from nitrite and used to protect organs from ischemia-reperfusion injury [48, 51].
Recycle of NO from nitrite and nitrate. Nitrate is reduced to nitrite, and subsequent reduction of nitrite forms NO. Reducing substances are deoxy-Hb [Hb(Fe2+)], myoglobin [Mb(Fe2+)], xanthine oxidase, hydrogen ion (H+), and cytochrome enzymes (Fe2+). NO2− is reduced by deoxy-Hb(Fe2+) to NO showing stoichiometric relation. Please count the number of O before and after the reduction responses.
In liver transplantation, the inhalation of 80 ppm NO until reperfusion ameliorates apoptosis, attenuated increases of liver enzymes, and enhanced the recovery of coagulation factors [48].
In orthopedic knee surgery, NO inhalation prevented increases in the adhesion molecule expression on granulocytes, plasma selectin levels, and NF-κB expression in quadriceps muscles [51]. NO inhalation was started before the tourniquet application and was continued during reperfusion until the completion of surgery.
After NO was identified as an endothelial cell-derived relaxation factor and following preclinical studies, iNO therapy has been studied extensively in multicenter randomized trials as well as in early pilot studies of infants with severe hypoxemia associated with PH or infants with congenital diaphragmatic hernia (CDH) [60]. These studies have demonstrated improved oxygenation and reduction in the need for extracorporeal membrane oxygenation (ECMO) therapy, leading to the approval of iNO therapy by the Food and Drug Administration for use in patients at >34-week gestation with hypoxemic respiratory failure and persistent PH of the newborn (PPHN). Over the last two decades, the discussion of its application has been extended to premature infants and acute pulmonary vascular response testing to assess indications for specific pulmonary vasodilator therapy for patients with PAH or operability for children with congenital heart disease.
Bronchopulmonary dysplasia (BPD), which is characterized by impaired pulmonary development resulting from insults affecting the immature lung, including inflammation, hyperoxia, and mechanical ventilation, is associated with high mortality and adverse long-term neurological and respiratory outcomes in infants born very preterm. Although the effectiveness of iNO for the treatment of PPHN is largely due to its function as a selective pulmonary vasodilator, laboratory observations also suggest other important biological effects of NO, such as roles in decreasing lung inflammation (e.g., lung vascular protein leak; pulmonary neutrophil accumulation) [61], reducing oxidant stress [62], decreasing pulmonary vascular cell proliferation [63], and enhancing alveolarization and lung growth [64, 65, 66]. These observations have led to investigations into the use of iNO to prevent the development of BPD in premature newborns. In an initial randomized, placebo-controlled study in a single center, 7 days of iNO prevented chronic lung disease in premature infants [67]. Despite promising findings in some subsequent studies showing a reduction in BPD in premature newborns [68, 69], later trials did not confirm the beneficial effects [70]. Meta-analyses of these studies have not found evidence for a net improvement in either chronic lung disease or developmental sequelae [71], leading to the conclusion by the National Institutes of Health Consensus Development Conference [72] and the American Academy of Pediatrics Committee on the Fetus and Newborn [73] that the use of iNO to prevent BPD is not supported by available evidence [74].
In addition to the use of iNO for BPD prevention, its use in preterm infants for acute management of severe hypoxemic respiratory failure has been discussed. Several case series have described responses to iNO in premature newborns with PPHN associated with prolonged oligohydramnios and pulmonary hypoplasia. Chock et al. evaluated a subset of 12 premature newborns enrolled in the Preemie Inhaled Nitric Oxide Trial with pulmonary hypoplasia after preterm premature rupture of membranes (PPROM) [75]. Six infants were treated with iNO with a mortality rate of 33% compared with 67% mortality for six infants in the placebo control group. Shah and Kluckow described outcomes for infants with PPROM and reported that survival improved from 62 to 90% after the introduction of iNO and high-frequency oscillatory ventilation [76]. Semberova et al. reported a series of 22 premature infants with a history of PPROM, pulmonary hypoplasia, and PPHN who were treated with iNO, with a survival rate of 86% [77]. Thus, iNO therapy may have important benefits in subgroups of preterm infants with severe PH, especially in patients with oligohydramnios and lung hypoplasia. Further studies of the precise effects of iNO in premature neonates are needed.
iNO in neonates with CDH has been evaluated in three randomized trials [78, 79, 80]. Finer and Barrington performed a Cochrane Review [81] of the use of iNO for respiratory failure in infants born at or near term. They concluded that while iNO might transiently improve oxygenation, its use is not recommended for infants with CDH because the risks of a composite of either death or ECMO are similar to or worse than those of controls [82].
Based on this evidence, iNO cannot be recommended for the routine treatment of PH in patients with CDH. However, iNO continues to be regularly used for CDH. Indeed, iNO was used at some point during preoperative stabilization in 36% (191/526) of infants with CDH from the population-based CAPSNet database. The ability of iNO to improve oxygenation and reduce the need for ECMO in non-CDH patients with PH explains its continued use in patients with CDH. The lack of a response to pulmonary vasodilators in CDH is speculated to be likely due to left atrial/pulmonary vein hypertension rather than to functional changes in the pulmonary arterial vasculature [83]. A recent study suggests that the response to pulmonary vasodilators in neonates with CDH may be limited by the severity of left ventricular (LV) dysfunction and/or hypoplasia, which impairs LV filling. Careful echocardiographic assessment, therefore, may guide treatment by identifying patients who may benefit from pulmonary vasodilators, including iNO [83].
The prognosis of children with PAH has improved in the past decade owing to new therapeutic agents and aggressive treatment strategies [84]. In idiopathic or heritable PAH (I/H-PAH), acute vasodilator testing (AVT) is recommended to identify patients who have a good long-term prognosis when treated with a long-term calcium channel blocker (CCB), accounting for 7–37% of children with PAH. For example, a >20% decrease in PAP or pulmonary vascular resistance (PVR) to inhaled NO accurately predicts a subsequent response to oral vasodilators, such as nifedipine. To identify such patients, the Sitbon criteria for positive AVT, as defined by a decrease in mean PAP by ≥10 mmHg to a value of <40 mmHg with an increased or unchanged cardiac output, is commonly used in adult I/H-PAH [85]. The Sitbon criteria can also be used to identify children who are expected to show a sustained response to CCB therapy [86]. Based on these data, the use of the Sitbon criteria is advised for AVT in children. Because only half of adult responders have a long-term hemodynamic and clinical improvement in response to CCB therapy, close long-term follow-up is required [87].
AVT (Figure 10) is also used to assess operability in children with PAH associated with a systemic-to-pulmonary shunt [87, 88]. Although pulmonary vasodilators other than iNO, such as inhaled iloprost or other orally or intravenously administered compounds (e.g., sildenafil and treprostinil), can be used for AVT, iNO ± oxygen is recommended [87]. The hemodynamic change that defines a positive response to AVT in PAH associated with a shunt (a ratio of pulmonary to systemic blood flow >1.5) for children should be a >20% decrease in PVR index and a ratio of pulmonary to systemic vascular resistance with respective final values of <6 Wood units m2 and <0.3. However, specific criteria for defining a positive AVT response that predicts the reversal of PAH and good long-term prognosis have not been described. The pediatric task force of the Sixth World Symposium on Pulmonary Hypertension agreed on a general guidance for assessing operability in CHD-PAH but emphasized that the long-term impact of defect closure in the presence of PAH with increased PVR is unknown [84].
Acute vasoreactivity testingto assess operability. AVT is also used to assess operability in children with PAH associated with a systemic-to-pulmonary shunt [87, 88]. (Figure 10, unpublished). A 5-month-old infant with Down syndrome and an atrial septal defect was evaluated for operability by acute vasoreactivity testing using inhaled nitric oxide. Pulmonary hemodynamic parameters at baseline, including pulmonary arterial pressure (76/29/49 mmHg), pulmonary vascular resistance index (6.7 Wood units m2), the ratio of pulmonary to systemic vascular resistance (0.45), and the ratio of pulmonary to systemic blood flow (1.74), are changed to 60/14/32 mmHg, 3.14 Wood units m2, 0.20, and 2.2 after nitric oxide inhalation, respectively. The patient underwent surgical closure of the shunt, and no postoperative pulmonary hypertension was observed. NO, nitric oxide; AO, aorta; PA, pulmonary artery.
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