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Oxidative stress and respiratory disorders

oxidative stress and respiratory disorders

Several studies suggest streess mitochondrial dysfunction is a predominant pathological oxidattive in all lung diseases [ 13, ]. Pinart M, Zhang M, Li F, Hussain F, Respirqtory J, Wiegman C, oxidative stress and respiratory disorders al. Strezs PubMed Google Disordets Gold PM. For instance, exposure to excess fine particulate matter, respirable fibers, inhalable quartz and metal powders, ozone, and vehicle exhaust from the environment causes oxidative stress, which initiates pulmonary inflammation, carcinogenesis, and fibrosis Valavanidis et al. The above data can be viewed and downloaded from VOSviewer1. Oxidative stress-driven pulmonary inflammation and fibrosis in a mouse model of human ataxia-telangiectasia. Catalase is involved in the detoxification of H 2 O 2 into molecular oxygen and water.

Oxidative stress and respiratory disorders -

Using S,R 3- 4-hydroxyphenyl -4,5-dihydroisoxazole acetic acid methyl ester ISO-1 which inhibits MIF tautomerase activity, the corticosteroid-insensitive lung inflammation and AHR after chronic ozone exposure was blocked Thus, inhibition of MIF which is elevated in COPD may provide a novel anti-inflammatory approach in COPD.

However, the contribution of mitogen-activated protein kinase phosphatase-1 MKP-1 that has been proposed to underlie CS insensitivity in COPD was found to be negligible in the chronic ozone model Single ozone exposure aggravated airway inflammation, airway remodeling, activation of p38 MAPK, and downregulation of MKP-1 in ovalbumin OVA -sensitized and -challenged mice, an effect that was ineffectively controlled by corticosteroids 46 , this also supported the role of p38 MAPK activation as a likely pathway involved in corticosteroid insensitivity Hydrogen sulfide H 2 S , a metabolic product of methionine, is synthesized from L-cysteine primarily by three key enzymes: cystathionine-c-lyase CGL , cystathionine-b-synthetase CBS and 3-mercaptypyruvate sulfurtransferase MPST.

In the lungs, H 2 S suppresses the airway smooth muscle proliferation and cytokine release, an effect that is less effective in muscle from COPD patients In addition, H 2 S content is reduced in the lungs of smokers and COPD patients , and H 2 S attenuates nicotine-induced endoplasmic reticulum stress and apoptosis in bronchial epithelial 16HBE cells H 2 S is able to prevent and treat the development of inflammation, AHR, and oxidative stress in acute ozone-exposed mice In addition, the ozone-induced increase in p38 MAK signaling was reduced in mice treated with H 2 S indicating that this intracellular signaling pathway might be involved In chronic ozone-exposed mice, H 2 S is also able to prevent the inflammation, AHR, and remodeling of the lung but is not able to reverse these hallmarks of the model Induction of p38 MAPK signaling is also reversed in both treatment strategies in the chronic ozone exposure model.

In addition to this, the activation of the NLRP3 inflammasome and the ratio between cleaved caspase-1 to pro-caspase-1 were positively correlated with changes in lung function parameters and structural changes in the lung.

H 2 S was able to prevent and treat the changes observed in NLRP3 activation Taken together, the main difference between the acute and chronic ozone exposure models on the treatment effects of H 2 S on the ozone-induced changes suggests that H 2 S treatment only affects the damage inducing pathways oxidative stress and not the regenerative pathways of the lung 92 , It is of interest that H 2 S donor NaHS significantly inhibits cigarette smoke-induced mitochondrial dysfunction, oxidative damage, cell senescence, and apoptosis in alveolar epithelial A cells These findings provide novel mechanisms underlying the protection of H 2 S against ozone and cigarette smoke-induced COPD and suggest that H 2 S donors targeted toward mitochondria may be beneficial in the treatment of COPD.

In addition to H 2 S, Belnacasan or VX inhibits NLRP3 inflammasome activation effects by inhibiting caspase In acute ozone exposed mice VX is able to prevent bronchoalveolar lavage BAL inflammatory markers, and AHR. Mitochondrial oxidative stress was reduced and this was associated with lower expression levels of dynamin-related protein 1 DRP1 and mitochondrial fission factor MFF , and increased expression of Mitofusin 2 MFN2 proteins involved in mitochondrial fission and fusion, respectively Similar effects were observed in chronic ozone exposed mice were VX is able to prevent inflammation, emphysema, airway remodeling, and oxidative stress while it decreased the expression of the fission protein DRP1 and MFF with affecting proteins involved in fusion dynamics.

Mitochondrial oxidative stress and NLRP3 inflammasome were driving ozone-induced inflammation processes and targeting these specifically might have therapeutic value in COPD. Apocynin, reduced nicotinamide adenine dinucleotide phosphate NADPH oxidase inhibitor decreased the proliferation in bronchial epithelium after an acute exposure to ozone but not the inflammation Ozone-induced inflammation, airway hyperreactivity, mitochondrial dysfunction, and ROS levels were reduced when chronically-exposed mice were pre-administered the mitochondrial directed antioxidant, MitoQ Similarly, ozone-induced inflammation, increased mitochondrial ROS, and expression of ETC complex II and IV in lung mitochondria in 6-week ozone exposed mice was reduced by treatment with mitoTEMPO, another mitochondria-targeting antioxidant However, airway remodeling and airflow obstruction were not Similarly, in single exposure to ozone, mitoTEMPO inhibited mitochondrial ROS without affecting inflammation and bronchial hyperresponsiveness In the chronic ozone exposure model, preventive NAC reduced the number of BAL macrophages and airway smooth muscle ASM mass while therapeutic NAC reversed AHR, and reduced ASM mass and apoptotic cells Thus, NAC could represent a treatment for protecting against the oxidative effects of ozone and other pollutants, as well as an agent for reducing exacerbations of COPD.

As documented above, several intracellular pathways have been implicated in the effects of single or multiple exposures to ozone in the mouse.

These pathways are related to the control of several key transcription regulatory factors including NF-κB, antioxidant factors such as Nrf2, the p38 MAPK, and priming of the immune system by up-regulating toll-like receptor expression.

Thus, in the single ozone exposure model, AHR and inflammation was inhibited by a c-jun NH2 terminal kinase JNK inhibitor SP , p38 MAPK inhibitor SD 46 , and NF-κB inhibitor VX, an inhibitor of NLRP3 inflammasome, prevented lung inflammation and AHR caused by acute exposure to ozone 53 , and also inhibited lung inflammation and emphysema from chronic exposure Mitochondrial transfer from induced pluripotent stem cell-derived mesenchymal stem cell iPSC-MSC offered protection against oxidative stress-induced mitochondrial dysfunction in human airway smooth muscle cells ASMC and in mouse lungs exposed to ozone while reducing airway inflammation and hyperresponsiveness Direct co-culture of ASMCs with iPSC-MSCs protected the former from cigarette smoke-induced mitochondrial ROS production, mitochondrial depolarization, and apoptosis.

When ASMCs were exposed to supernatants from iPSC-MSCs or transwell inserts with iPSC-MSCs, only cigarette smoke-induced mitochondrial ROS, but not mitochondrial depolarization and apoptosis in ASMCs, were improved, indicating that soluble factors from iPSC-MSCs reduced production of mitochondrial ROS.

When there was direct contact between iPSC-MSCs and ASMCs, mitochondria were transferred from iPSC-MSCs to ASMCs, possibly through formation of tunneling nanotubes, an effect that was enhanced by cigarette smoke medium CSM treatment.

iPSC-MSCs prevented, but did not reverse, ozone-induced mitochondrial dysfunction, AHR, and airway inflammation in the mouse model of single ozone exposure, an effect resulting from direct interaction and mitochondrial transfer between iPSC-MSCs and airway cells. Therefore, transfer of mitochondria from IPSC-MSC cells to replace damaged mitochondria by oxidative stress may present a novel approach to treating conditions such as COPD.

As an important component of air pollution, ozone has been closely related to the development of COPD. The link comes from two sides: on the one hand, chronic exposure to ozone in murine model of lung inflammation and emphysema and on the other, long-term exposure to ambient air pollutant such as ozone, has been associated with increases in emphysema evaluated by computed tomographic imaging with chronic airflow obstruction.

The mechanisms of ozone-induced lung and airway changes are the release of inflammatory factors such as IL-1α, IL-6, IL-8, CXCL, CCL2, ICAM-1, KEAP-1, and MIF, the activation of intracellular pathways such as the MAPK pathway, TLR, cell death pathways, NLRP3 inflammasome, and NF-κB, the induction of oxidative stress through a decrease in the antioxidative response and an increase in the production of ROS, with a detrimental effect on mitochondrial function such as increased mitochondrial ROS, decreased ATP content and abnormal ETC complex Figure 1.

Other mechanisms include the disruption of airway epithelial barrier, the development of AHR and emphysema and the state of CS insensitivity. Figure 1. Ozone-mediated effects on intracellular pathways involved in cell injury and inflammation.

Overview of the effects of ozone in in vitro and in vivo models. The biphasic response to ozone starts with an immediate intracellular reactive oxygen species ROS and inflammation independent phase that is induced by extracellular oxidative stress.

ROS induces membrane damage with changes in cell membrane integrity, disruption of tight junctions, epithelial cell stress, and death. Inflammatory mediators including IL and IL are released and attract innate immune cells such as natural killer NK cells and innate lymphoid type 2 ILC2 cells.

Processes activated during the intracellular ROS and inflammation-dependent phase of the effects of ozone include transcription factor-mediated inflammatory response and the activation of the antioxidant defense mechanism. Several inhibitors have been shown to prevent or treat the pro-inflammatory gene expression and subsequently inhibit the inflammatory response, including the JNK inhibitor, SP, and the p38 MAPK inhibitor, SD In addition, activation of the endogenous antioxidant defense system involving HADC2, Keap1, and Nrf2 may be sufficient to counteract the oxidant stress during acute ozone exposure but may be overwhelmed during chronic ozone exposure.

Treatment with the antioxidant N-acetylcysteine NAC also reduces the inflammatory response, by scavenging of intracellular ROS with subsequent reduction of cytokine and chemokine production. Mitochondrial oxidative stress and mitochondrial dysfunction contribute to apoptotic processes and the activation of the NLRP3 inflammasome further enhancing the inflammatory response.

Several treatment strategies targeting the mitochondria have been able to reduce or prevent the mitochondrial oxidative-induced dysfunction. These include several mitochondrial-targeted antioxidants such as MitoQ, MitoTEMPO, and SS In addition, stem cell therapy with induced pluripotent stem cell-derived mesenchymal stem cells iPSC-MSCs prevented ozone-induced mitochondrial dysfunction and inflammation which may result from direct interaction and mitochondrial transfer between the iPSC-MSCs and airway cells.

Treatment with the caspase-1 inhibitor VX and hydrogen sulfide H 2 S prevent the activation of the inflammasome and reduces inflammation and mitochondrial oxidative stress. The MIF inhibitor ISO-1 blocks the ozone exposure induced inflammation and airway hyperreactivity and might have an impact on the corticosteroid insensitivity present in chronic ozone exposed lungs.

Corticosteroids reduce inflammation induced by acute ozone exposures but fail to affect these processes in the steroid insensitive chronic ozone exposed lung.

The ozone exposure driven intracellular processes contribute to the inflammatory cytokine and chemokine production, immune cell recruitment, and eventually the development of airway hyperreactivity, airway obstruction, airway remodeling, emphysema, autoimmunity, and steroid insensitivity which are hallmarks of COPD.

CW, FL, DT, and KC wrote the review. KC and BR inspired the work and corrected the manuscript. All authors have read the contribution.

This work was supported by Center National de la Recherche Scientifique CNRS , European Regional Development Fund FEDER N and EX , Respir Ozone N , The Wellcome Trust KC , the Key International Regional Cooperative Project of the National Natural Science Foundation of China Grant No.

LF was supported by the National Nature Science Foundation of China The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Learn about institutional subscriptions. Table of contents 22 chapters Search within book Search. Page 1 Navigate to page number of 2. Front Matter Pages i-xvi. General Aspects of Reactive Oxygen Species-Mediated Lung Diseases Front Matter Pages The Effects of Free Radicals on Pulmonary Surfactant Lipids and Proteins Mustafa Al-Saiedy, Francis Green, Matthias Amrein Pages Oxidative Stress in Experimental Models of Acute Lung Injury Daniela Mokra, Juraj Mokry Pages Potential of Mesenchymal Stem Cells in Modulating Oxidative Stress in Management of Lung Diseases Rituparna Chaudhuri, Manisha Singh, Sujata Mohanty Pages Role of NADPH Oxidase-Induced Oxidative Stress in Matrix Metalloprotease-Mediated Lung Diseases Jaganmay Sarkar, Tapati Chakraborti, Sajal Chakraborti Pages Oxidative Stress Mechanisms in the Pathogenesis of Environmental Lung Diseases Rajesh K.

Thimmulappa, Indranil Chattopadhyay, Subbiah Rajasekaran Pages Chronic Lung Diseases Front Matter Pages Oxidative Stress-Induced Mitochondrial Dysfunction and Asthma Samarpana Chakraborty, Kritika Khanna, Anurag Agrawal Pages Regulation of Antioxidant Nrf2 Signaling: An Important Pathway in COPD Nirmalya Chatterjee, Debamita Chatterjee Pages Role of Oxidative Stress Induced by Cigarette Smoke in the Pathogenicity of Chronic Obstructive Pulmonary Disease Anuradha Ratna, Shyamali Mukherjee, Salil K.

Das Pages Oxidative Stress in Obstructive and Restrictive Lung Diseases Elena Bargagli, Alfonso Carleo Pages TRP Channels, Oxidative Stress and Chronic Obstructive Pulmonary Disease Amritlal Mandal, Anup Srivastava, Tapati Chakraborti, Sajal Chakraborti Pages Paraquat-Induced Oxidative Stress and Lung Inflammation Namitosh Tyagi, Rashmi Singh Pages Environmental and Occupational agents and Cancer Drug-Induced Oxidative Stress in Pulmonary Fibrosis Tapati Chakraborti, Jaganmay Sarkar, Pijush Kanti Pramanik, Sajal Chakraborti Pages Other Lung Diseases Front Matter Pages Respiratory Syncytial Virus-Induced Oxidative Stress in Lung Pathogenesis Yashoda Madaiah Hosakote, Kempaiah Rayavara Pages Reactive Oxygen Species: Friends or Foes of Lung Cancer?

Deblina Guha, Shruti Banerjee, Shravanti Mukherjee, Apratim Dutta, Tanya Das Pages Role of Noncoding RNA in Lung Cancer Angshuman Bagchi Pages Reactive Oxygen Species ROS : Modulator of Response to Cancer Therapy in Non-Small-Cell Lung Carcinoma NSCLC Shamee Bhattacharjee Pages Back to top.

About this book This is the second volume of the comprehensive, two-volume work on oxidative stress in lung diseases. Editors and Affiliations Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, India Sajal Chakraborti, Rita Ghosh, Tapati Chakraborti Department of Internal Medicine, The Ohio State University, Columbus, USA Narasimham L.

Ganguly Back to top. About the editors Prof. Tapati Chakraborti is a Professor of Biochemistry at the University of Kalyani, West Bengal, India.

Her research focuses on the determination of the Mechanisms Associated with the Role of Proteases in the Oxidant-mediated Cellular Dysregulation of Pulmonary Vascular Endothelial and Smooth Muscle Cells.

COPD is a major and increasing global health problem and is currently the third leading cause of death in the world [ 1 ]. COPD is defined as a preventable and treatable disease characterized by persistent airflow limitation that is not fully reversible [ 2 ].

The airflow limitation is usually progressive and associated with an enhanced chronic inflammatory response of the airways and the lungs to noxious particles or gases.

Exacerbations and comorbidities contribute to the overall severity in individual patients [ 2 , 3 ]. COPD results from the interplay between genetic susceptibility and exposure to environmental stimuli [ 4 ].

A well established genetic cause of COPD is α 1 antitrypsin deficiency [ 5 ] whereas, among environmental stimuli, cigarette smoking is the main cause. Other exposures, such as outdoor air pollution, occupational exposure to dusts and fumes, exposure to second-hand smoke, and biomass smoke inhalation might increase the risk of and lead to disease in nonsmokers [ 6 , 7 ].

Cigarette smoke in particular contains 10 17 oxidant molecules per puff [ 8 ]. Such exposure causes direct injury of airway epithelial cells leading to airway inflammation in which a variety of cells such as neutrophils, macrophages and lymphocytes, are involved.

Proteolytic enzymes and reactive oxygen species ROS are released and, if not sufficiently counterbalanced by antiproteases and antioxidant factors, will produce further damage [ 9 ]. Formation of ROS takes place constantly in every cell during normal metabolic processes.

Moreover, activated phagocytic cells such as neutrophils and macrophages produce large amounts of ROS when are stimulated by encounter inhaled particles or other mediators of inflammation [ 10 ]. When ROS are produced in excess of the antioxidant defense mechanisms, oxidative stress occurs resulting in harmful effects, including damage to lipids, proteins and DNA.

Although the pathogenesis of COPD remains incompletely understood, the central role of oxidative stress in this regard is well established Fig.

A mechanism showing the central role of oxidative stress in the pathophisiology of COPD. The imbalance between oxidants and antioxidants in favor of oxidants leads to harmful damage. Oxidative stress amplifies the inflammatory response influencing intracellular signaling pathways that drive the release of inflammatory mediators, impairing fagocytosis of apoptotic cells and weakening the ability of corticosteroids to repress proinflammatory genes expression.

Inflammation, lipid peroxidation, protein oxidation and DNA damage results in tissue damage, alteration of protein functions and gene expression, remodeling of extracellular matrix and mucus secretion. Several biomarkers of oxidative stress are available, including ROS themselves.

Since ROS are generally too reactive and have a half-life too short to allow their direct measurement in tissues or body fluids, it is more suitable to estimate oxidative stress by measuring their oxidation target products, including lipid peroxidation end products and oxidized proteins, as well as various antioxidants [ 15 ].

Regarding COPD, various biomarkers of oxidative stress have been evaluated, both oxidant and antioxidant markers. In this review we summarize the main findings about oxidative stress biomarkers grouped according to their method of detection, evaluated in the blood of COPD patients compared to healthy controls as well as in different stages of the disease.

The majority of these studies have considered from mild to very severe COPD while very few studies, to our knowledge, have considered only mild COPD subjects for their analysis. Lipid peroxidation is the major consequence of oxidative stress and cause of oxidative damage [ 16 ].

Many evidences show the association between the levels of these biomarkers and the development of various diseases [ 15 , 17 , 18 ]. Accordingly, lipid peroxidation products have received much attention as biomarkers of oxidative stress.

Lipids are vulnerable to oxidation by both enzymes and nonenzymatic oxidants. The mechanisms and products of lipid peroxidation have been studied extensively [ 19 , 20 ]. Polyunsaturated fatty acids are very reactive toward oxygen radicals and readily oxidized to produce lipid hydroperoxides and various aldehydes as major products.

Cholesterol is also an important substrate of oxidation and its oxidation products are also studied as biomarkers of oxidative stress [ 21 ]. Various biomarkers of lipid peroxidation have been developed and applied to biological samples [ 22 ].

Among these, malondialdehyde MDA and thiobarbituric acid reactive substances TBARS remain among the most commonly applied indices of oxidative damage [ 23 , 24 ]. Several studies have investigated MDA as potential biomarker to assess oxidative stress status in COPD patients using the method of TBARS that involves the reaction of MDA with thiobarbituric acid TBA under strong acidic condition and heating, leading to the formation of an adduct which can be easily assessed with a spectrophotometer.

One of the most consistent finding across many of these studies was a significant increase in TBARS MDA in COPD patients compared to healthy controls [ 25 — 45 ] Table 1.

Moreover, using this kind of approach some authors have investigated the levels of plasma MDA in parallel with the progression of the disease, observing both an increase with increasing severity of the disease [ 26 , 29 , 46 , 47 ] and no differences [ 40 ] Table 1.

Conversely, few other authors did not find a significant difference in plasma TBARS MDA of COPD patients compared to healthy controls [ 48 — 53 ] Table 1 , while others described a significant increase during acute exacerbations and a return to values comparable to those of controls by the time of discharge after treatment [ 54 ].

We investigated MDA levels considering only mild COPD, finding no differences between patients and controls [ 55 ] Table 1. Some authors have analyzed MDA measuring TBA-MDA adduct with high performance liquid chromatography HPLC rather than spectrophotometer and finding a significant increase of this biomarker in COPD compared to healthy controls [ 56 , 57 ] Table 1.

Moreover, measuring free MDA, not as TBA-MDA adduct, by means of HPLC using an ultraviolet spectrophotometric detector at the wavelength of nm, a significant increase of this biomarker has also been found in exacerbated COPD, as well as after treatment of the exacerbation compared to healthy controls [ 58 ] Table 1.

By using a different assay that involves 1-methylphenylindole, that under acidic and mild-temperature conditions reacts with MDA to yield a stable chromophore with maximal absorbance at nm, an increase of plasma MDA levels has been described [ 59 — 61 ], in some cases also in relation to disease progression [ 59 , 60 ] Table 1.

To a lesser extent than MDA, other biomarkers of lipid peroxidation have been studied in plasma of COPD patients of which have been described increased levels compared to controls Table 1 : lipid peroxides, determined spectrophotometrically either using their ability to convert iodide to iodine in a solution containing cholesterol-iodide [ 59 ] or following their reaction with peroxidase and a subsequent color production [ 62 ]; conjugated dienes, that are formed in the process of lipid peroxidation as a result of a reconfiguration of double bonds and yield a characteristic absorbance peak [ 27 , 59 ]; oxidized LDL, determined spectrophotometrically with a competitive enzyme-linked immunosorbent assay ELISA kit [ 62 ] and 8-isoprostane, assayed with a specific enzyme immunoassay kit [ 63 ].

The most abundant byproduct of oxidative damage of proteins is protein carbonylation [ 64 ]. The presence of carbonyl groups in proteins is therefore the most commonly used marker of ROS mediated protein oxidation [ 64 , 65 ], and accumulation of protein carbonyls has been observed in several human diseases [ 64 , 66 , 67 ].

Specifically, carbonyl derivatives aldehydes and ketones are formed by reaction of oxidants with lysine, arginine, proline, and threonine residues of the protein side-chains. Moreover, direct reactions of proteins with ROS may also lead to the formation of peptide fragments containing highly reactive carbonyl groups.

Proteins containing reactive carbonyl groups can also be generated by secondary reactions of lysine residues of proteins with reducing sugars or their oxidation products and also by reactions of lysine, cysteine, or histidine residues with unsaturated aldehydes formed during the peroxidation of poly-unsaturated fatty acids [ 68 ].

The most common and reliable method for determination of carbonyl content is based on the reaction of carbonyl groups with 2,4-dinitrophenylhydrazine DNPH , which leads to the formation of a stable dinitrophenylhydrazone DNP product that can then be detected and quantified spectrophotometrically at nm or immunochemically using specific antibodies to anti-DNP [ 67 ].

The approach based on the reaction of carbonyl groups with DNPH has been used in several studies to investigate protein carbonylation levels in the plasma of COPD patients, both detecting DNP product spectrophotometrically [ 29 , 35 , 36 , 40 , 59 , 60 , 69 ] and immunochemically [ 46 , 70 , 71 ] Table 1.

All of these studies have described a significant increase of protein carbonyl groups in plasma of COPD patients, that sometimes [ 59 ], but not always [ 29 , 36 , 40 ] proceeds in parallel with the progression of the disease Table 1. On the other hand, few other studies observed no differences in this biomarker levels using the same kind of approach [ 72 , 73 ] Table 1.

However, a significant increase in plasma protein carbonylation levels has been described also using another kind of assay, that is by labeling protein carbonyl groups with tritiated borohydride [ 52 ] Table 1.

In this study the authors described an increase in the amount of plasma carbonyls in parallel with the progression of COPD. To estimate the degree of oxidant-mediated protein damage in plasma of COPD patients, the presence of advanced oxidation protein products AOPP has also been investigated.

AOPPs are a family of oxidized, dityrosine-containing, cross linked protein compounds formed by the reaction of plasma proteins, especially albumin, with chlorinated oxidants [ 74 ]. Measuring this parameter in a spectrophotometer on a microplate reader [ 75 ], both an increase [ 32 , 40 ] and no difference [ 49 ] has been described in plasma of COPD patients compared to controls Table 1.

This marker has been considered in the course of disease progression too, finding no difference throughout the stages of the disease [ 40 ] Table 1. Instead of measuring different oxidant species separately, some authors have studied total oxidative status TOS in plasma of COPD patients as a marker of oxidative stress, named also total peroxide TP or reactive oxygen metabolites ROMs [ 77 ].

TOS can be evaluated by means of an assay based on the oxidation of ferrous ion to ferric ion by the oxidants present in the sample.

The ferric ion makes a colored complex with xylenol orange and the color intensity can be measured spectrophotometrically.

Using this assay, an increase in TOS has been described in COPD [ 32 , 78 — 80 ]. Other authors have measured ROMs in plasma of COPD patients to test the oxidant ability of the plasma sample towards a particular substance used as an indicator. By means of the so called diacron reactive oxygen metabolites D-ROM test, an increase of overall ROMs has been described in COPD patients compared to controls [ 81 , 82 ].

To a lesser extent than other oxidative stress biomarkers, oxidatively damaged DNA has been studied in COPD patients as well.

A sensitive method for analyzing oxidative DNA damage is the single-cell gel electrophoresis also known as comet assay, which detects strand breaks [ 83 ]. Breaks in DNA allow supercoiled loops of DNA to relax and move out to form what looks like a comet with a tail under the conditions of the assay.

The proportion of DNA in the tail is indicative of the frequency of breaks. By means of this assay, a significant increase in DNA damage has been detected in COPD compared to controls [ 35 , 40 , 84 ]. No significant difference in levels of DNA damage, as measured by 8-oxodG by means of ELISA [ 71 ] or HPLC [ 57 ], has been found.

The plasma thiol pool is mainly formed by protein thiols and slightly formed by low molecular-weight thiols, such as cysteine, cysteinylglycine, glutathione GSH , homocysteine, and γ-glutamylcysteine [ 85 ] and are considered a key factor in redox sensitive reactions of plasma [ 86 ].

In fact, thiols can undergo oxidation processes in the presence of oxidants to yield a wide range of products, some of which, like disulfides, can revert to thiols with suitable reductants, while others such as sulfinic and sulfonic acids constitute typically final products [ 85 , 87 ].

Thus, as well as intracellular thiols, such as GSH, are essential in maintaining the highly reduced environment inside the cell, extracellular thiols also constitute an important component of the antioxidant defense system [ 88 , 89 ]. The most abundant reduced -SH group in plasma is that of human serum albumin, given its high concentrations.

This compound is reduced by free thiols in an exchange reaction, forming a mixed disulphide and releasing one molecule of 5-thionitrobenzoic acid, which can be measured at nm [ 91 ]. This method of detection has been used in several studies to measure the content of both protein and non-protein SH groups in the peripheral blood of COPD patients.

Some authors have investigated this biomarker in the different stages of severity of COPD finding no differences [ 29 , 36 ]. Interestingly, other authors found a significant reduction of protein SH groups only in exacerbated COPD [ 39 , 54 ] with a complete restoration by the time of discharge after treatment of exacerbation [ 54 ].

Measuring SH groups by analysis of albumin on a chemistry automated analyzer, a significant reduction of protein thiols has been detected [ 56 ] Table 1. A significant decrease in non-protein SH groups, mainly in the form of reduced GSH, has been found in many of the examined studies [ 28 , 34 , 40 , 41 , 43 , 45 , 53 ] Table 1.

No differences have been found considering only mild COPD [ 55 ] Table 1. When investigated in the different stages of COPD severity, no difference has been found, either [ 40 ] Table 1. Analyzing protein and non-protein SH groups as total thiols, a significant reduction of this marker has been found in COPD compared to controls [ 51 ], as well as with progression of the disease [ 40 ], while other authors found that the concentration of total thiols was enhanced in plasma of COPD patients compared to controls [ 69 ] Table 1.

By means of spectrophotometric or chromatographic methods, the plasmatic levels of some antioxidant nutrients such as vitamin A, C and E and α- and β-carotenes that comprise an important aspect of the antioxidant defense system evolved by humans, have been investigated.

A decreased level of vitamin C [ 25 , 28 , 62 ] and E [ 25 , 28 , 30 ], as well as no difference in the levels of vitamin A [ 27 ], C [ 40 , 48 , 95 ] and E [ 27 ] has been described in COPD compared to healthy controls.

No differences have also been found in the different stages of severity of disease [ 96 ]. A significant reduction of vitamins A, C and E has been described in exacerbated COPD, with a restoration to values similar to that of controls after exacerbation treatment [ 58 ].

A significant decrease of α- and β-carotenes has also been described in plasma of COPD patients compared to healthy controls [ 84 ]. In particular, the plasma levels of selenium Se and zinc Zn , determined by inductively coupled plasma-mass spectroscopy, have been evaluated, finding decreased levels in COPD compared to controls [ 62 ].

Measuring Se, Zn, iron Fe , copper Cu , potassium K , rubidium Rb and calcium Ca by particle-induced X-ray emission, a reduction of K and Se and an increase of Fe, Ca, Cu, Zn and Rb has been described in plasma, while in the blood cells of the same COPD patients a reduction of K and Rb and an increase of the other elements studied has been described [ 69 ].

Measuring Cu and Zn by means of atomic absorption spectrophotometry a significant increase of Cu and no difference for Zn has been found [ 44 ]. Uric acid is a powerful antioxidant that protects lipoproteins from oxidation and acts as a powerful scavenger of individual oxygen radicals and hydroxyl radicals.

Significantly decreased levels of uric acid have been found by means of an enzymatic method using a colorimetric assay in plasma of COPD subjects compared to healthy controls [ 97 ] whereas a significant decrease was found only in very-severe COPD by HPLC with electrochemical detection [ 95 ].

No difference has been found using an automated analyzer [ 49 ]. Given the difficult to measure each antioxidant separately, several methods have been developed and used to determine the total antioxidant capacities of various biological samples [ 98 ].

Some of these methods have been applied to determine the total antioxidant status in the plasma of COPD patients, in particular the FRAP ferric reducing ability of plasma and the TEAC Trolox Equivalent Antioxidant Capacity assay. The ABTS radical cation is formed when ABTS is incubated with the peroxidase metmyoglobin and H 2 O 2.

Upon the addition of a plasma sample, the oxidative reactions are suppressed by the antioxidant capacity of the plasma, preventing the color change. Using the FRAP assay a significant decrease of total antioxidant capacity has been found in COPD patients compared to controls [ 29 , 36 ] in relation also to disease progression [ 29 , 36 , 96 ].

Using the TEAC assay, a significant decrease of total antioxidant capacity [ 40 , 54 , 92 , 97 , 99 , ] as well as no significant difference [ 49 ] has been described in COPD compared to controls. Moreover, other authors found a significant reduction only in exacerbated COPD [ 39 ].

The TEAC assay has been used also to investigate this biomarker in relation to disease progression, finding no difference throughout the various stages of the disease [ 40 ].

By means of another assay based on preventing the oxidation of ortho-dianisidine molecules into dianisidyl radicals by hydroxyl radicals, a significant decrease of total antioxidant potential has been described in COPD compared to controls [ 79 ].

Some antioxidant enzymes have been widely studied in blood of COPD patients such as superoxide dismutase SOD , catalase and glutathione peroxidase GSH-Px. To a lesser extent, the activities of glutathione-S-transferase GST , paraoxonase 1 PON1 and ceruloplasmin ferroxidase have also been studied.

In most studies SOD activity has been measured in COPD erythrocytes with the Mc Cord and Fridovich assay [ ] finding different results Table 1.

SOD inhibits this reaction and the activity is measured as percent inhibition. Using this method, either an increase [ 36 , 69 ] or a decrease [ 99 , ] of erythrocytes SOD activity, as well as no difference [ 33 ] has been found in COPD versus controls Table 1.

No differences have also been found comparing moderate and severe COPD [ 46 ] Table 1. Moreover, an increase in erythrocytes SOD activity has been observed only in exacerbated COPD [ 38 ]. Other assays measure SOD activity taking advantage of its ability to inhibit various reactions such as the auto oxidation of epinephrine to adrenochrome [ ], the auto oxidation of pyrogallol [ ] and the nitrite formation subsequent to reactions of O 2 - with hydroxylamine hydrochloride [ ].

The use of these assays brought different results. It has been found both a decrease [ 26 , 29 , 30 ] and an increase [ 27 ] of erythrocyte SOD activity as well as no difference compared to controls [ 40 ] Table 1. SOD activity has been determined also in plasma of COPD patients using assays based on the inhibition of red formazan dye formation, finding an increase of SOD activity [ 61 ], a decrease of SOD activity [ 32 , 41 ] and no difference [ 70 , 71 ] compared to controls, as well as no difference throughout the stages of the disease [ 47 ] Table 1.

Estimating SOD with an ELISA kit, a significant reduction has been found in COPD subjects compared to controls [ ] Table 1. Catalase is involved in the detoxification of H 2 O 2 into molecular oxygen and water. Its activity has been measured in COPD erythrocytes using different methods based on monitoring the decomposition rate of H 2 O 2 at nm.

In such way, both a decrease [ 26 , 29 , 99 , ] and no difference [ 27 , 33 , 36 , 40 ] of catalase activity has been observed in COPD compared to controls Table 1. Studying catalase activity in relation to disease progression has also brought different results, namely a significant decrease from moderate to severe COPD [ 26 ] as well as no difference either comparing moderate and severe COPD [ 46 ] or comparing all the stages of the disease [ 40 ] Table 1.

Catalase activity has been measured also in plasma in few studies where both a decrease [ 34 , 43 ] and no significant difference [ 47 , 71 ] has been observed in COPD compared to controls Table 1. Moreover, estimating the enzyme activity with an ELISA kit, no significant difference has been found [ ] Table 1.

GSHPx activity converts reduced GSH to GSSG while reducing organic peroxides into their corresponding alcohols or H 2 O 2 into water.

Its activity has been measured in plasma, in total blood and especially in erythrocytes evaluating at nm the oxidation of nicotinamide adenine dinucleotide phosphate NADPH , a coenzyme in the reaction catalyzed by glutathione reductase that reduces GSSG formed during the activities catalized by GSHPx.

In most of the studies a decreased GSHPx activity in COPD erythrocytes has been described compared to controls [ 26 , 27 , 29 , 33 , 36 , 99 ] as well as in relation to disease severity [ 46 , ] Table 1. A decreased GSHPx activity has been observed analyzing COPD total blood [ 69 ] and plasma [ 34 , 41 , 43 ] Table 1.

In plasma, no difference in GSHPx activity [ 61 ] as well as an increase either monitoring the rate of NADPH oxidation [ 36 , ] or assaying the content of reduced GSH [ 40 ] has also been observed Table 1. GST catalyzes the inactivation of reactive electrophiles through their conjugation with GSH while PON1, an esterase associated with high-density lipoprotein HDL , protects against the toxicity of some organophosphates and contributes to the antioxidant protection conferred by HDL on low-density lipoprotein oxidation.

GST activity has been studied using 1-chloro- 2,4-dinitrobenzene as an artificial substrate in plasma of COPD finding a decreased activity [ 99 ] and no differences compared to controls [ 61 ] as well as in erythrocytes [ 26 ] where a decreased enzymatic activity has been described.

Using the first method no significant difference has been described in COPD compared to controls [ 32 , 78 ]. Using the paraoxon method, a significant decreased enzyme activity has been described, either in COPD versus controls [ 44 ] and in the different stages of severity of disease [ 59 ].

No significant difference was found when only mild COPD was considered [ 55 ]. Ceruloplasmin is an important contributor to plasma antioxidant activity that includes ferroxidase activity, GSH-Px activity and the ability to scavenge ROS [ ].

Its oxidase activity has been investigated in plasma of COPD subjects by means of an assay that works on its ability to oxidize ferrous ion to ferric ion, complexing with a chromogen that can be measured at nm. With this technique, a significant increase of the enzyme activity in COPD has been found [ ] as well as no significant difference [ ].

By means of immunonephelometry on an automated analyzer a significant increase of ceruloplasmin was found in COPD [ 56 ]. GGT is a plasma membrane enzyme, which is involved in antioxidant glutathione resynthesis.

Serum GGT levels are increased in a number of diseases that are known to have oxidative stress in the pathogenesis, suggesting that GGT levels can be considered a marker of oxidative stress [ , ]. GGT activity has been investigated in plasma of COPD patients.

By using standardized methods on automatic analyzer, a significant increase of the enzyme activity has been found in COPD compared to healthy controls [ ] as well as no difference [ ].

A significant increase of GGT activity has also been found in exacerbated COPD compared to stable state [ ] whereas no differences have been found in the different stages of the severity of the disease [ ].

In this review we have summarized the main findings about the most studied circulating biomarkers of oxidative stress in COPD subjects, grouping them depending on the method of detection that could be useful for those who wants to deal with this issue.

Although oxidative stress has been largely studied in COPD, we still lack standardized biomarkers useful in diagnosis and in monitoring the progression of the disease. What emerges from literature is that lipid peroxidation products are the most studied as biomarkers of oxidative stress in COPD, especially MDA.

In most cases it has been reported an increase of this marker either as MDA or as lipid peroxides, 8-isoprostane, conjugated dienes or oxidized LDL.

A marker of oxidative stress that, to our knowledge, has been described always increased in the examined case—control studies is superoxide anion, even if different assays have been used to investigate this marker. In addition, total oxidative status has been described always increased as well, by means of two types of assays and also in mild COPD.

the sample collection, the time that elapses between collection of the sample and separation of serum from the blood cells, and the storage of the sample temperature storage, container used for storage and repeated thawing.

We must also consider the biological variability, due to age, sex, race and genetic selection. All of these variables unavoidably influence the measurement. Regarding antioxidant markers, protein and non protein SH groups have been largely investigated giving different results especially for the latters that have been studied in plasma, in erythrocytes and in whole blood.

On the contrary, conflicting results have been found analyzing the levels of antioxidant nutrients, such as vitamins A, C and E, and the enzymatic antioxidant activities. In fact, some authors have found a significant decrease of these biomarkers, while others have found no significant difference.

These conflicting findings could be due not only to the reasons explained above regarding the pre-analytical steps, but also to the fact that studies were carried out in different populations, and that there may be differences and inter-individual variations in antioxidant capacity, also due to cigarette smoke and its effect on the imbalance between oxidants and antioxidants.

From an overall point of view, despite the difficulties in reproducing the same results using different assays in different research laboratories, the findings summarized in this review highlight that literature is quite concordant in concluding that the blood of COPD patients presents an increase of oxidants and a decrease in some antioxidant defences compared to controls.

Up to now a large number of biomarkers have been evaluated in COPD, but their relative importance is not yet clearly understood. Hence, there is clearly the need to identify suitable biomarkers able to detect disease, to monitor disease progression, exacerbations and response to therapy.

For this purpose, the choice of peripheral blood among other biological matrices, seems to be more appropriate given the non invasiveness of the blood sampling, its property of easily allowing repeated measurements and its effectiveness in monitoring systemic effects such as oxidative stress.

Surely, further research is needed to validate such markers and a great effort should be done to better characterize subjects under study and to understand the issues that likely influence the measurements.

Anyhow, this review is an important step in this context providing a comprehensive overview of the oxidative stress biomarkers evaluated in the blood of COPD subjects, stressing their potential utility in supporting diagnostic and therapeutic decisions. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, et al.

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Am J Respir Crit Care Med. Pryor WA, Stone K. Oxidants in cigarette smoke: radicals, hydrogen peroxides, peroxynitrate, and peroxynitrite. Ann N Y Acad Sci. Larsson K. Aspects on pathophysiological mechanisms in COPD.

J Intern Med. Rahman I, Biswas SK, Kode A. Oxidant and antioxidant balance in the airways and airway diseases. Eur J Pharmacol. Kirkham PA, Barnes PJ. Oxidative stress in COPD. MacNee W. Oxidative stress and lung inflammation in airways disease. Proc Am Thorac Soc. Fischer BM, Voynow JA, Ghio AJ.

COPD: balancing oxidants and antioxidants. Int J Chron Obstruct Pulmon Dis. Article CAS PubMed PubMed Central Google Scholar. Dalle-Donne I, Rossi R, Colombo R, Giustarini D, Milzani A. Biomarkers of oxidative damage in human disease. Clin Chem. Niki E. Lipid peroxidation: physiological levels and dual biological effects.

Free Radic Biol Med. Lipid peroxidation products as oxidative stress biomarkers. Giustarini D, Dalle-Donne I, Tsikas D, Rossi R.

Department of Biochemistry and Oxidative stress and respiratory disorders, Oxidatife of Qnd, Kalyani, India. You can also search for this editor in Tsress Google Scholar. Disordefs of Internal Medicine, Oxidative stress and respiratory disorders Ohio State University, Columbus, USA. Adopts a multidisciplinary approach, demonstrating cellular and molecular mechanisms associated with ROS-induced initiation and progression of a variety of lung diseases. Covers pathological aspects of oxidative stress induced initiation and progression of different types of lung disease, including COPD, asthma and their potential therapeutics known to date.

Oxidative stress and respiratory disorders -

The common environmental agents that trigger asthma include aeroallergens indoor and outdoor , tobacco smoke, dust, air pollutants, cold air and viruses. The hallmark pathological features of asthmatic airways include airway remodeling, epithelial desquamation, goblet cell hyperplasia and inflammation and are associated with eosinophils, mast cells, neutrophils, macrophages and T helper type 2 cells Th2 cells [ 47 ].

In asthmatics lungs, allergen exposure triggers immunoglobulin E IgE production from B cells, degranulation of mast cells and infiltration of eosinophil into airways.

These events are mediated by Th2 cytokines, namely, IL, IL-4, IL-5 and IL Th1 cytokines IFN-g, IL and Th17 cytokines IL are implicated in severe or steroid resistance asthma, which is characterized by high neutrophilic inflammation.

Acute lung injury and its severe form ARDS are common complications in patients admitted to intensive care unit. ARDS results from direct or indirect injury to lungs.

Direct injury may be caused by gastric aspiration, pneumonia, inhalation of injuries gases and pulmonary contusion. Indirect injury includes sepsis, pancreatitis and trauma.

ARDS is characterized by alveolar flooding with protein-rich oedema followed by a progressive fibrotic phase [ 49 ]. Pathogenesis of ARDS involves an early injury to alveolar epithelium and capillary endothelium, which results in leakage and flooding of alveolar and interstitial spaces with protein-rich oedema.

This is also accompanied by a massive influx of neutrophils into alveolar and interstitial spaces. Neutrophils secrete proteolytic enzymes elastase and metalloprotease , ROS, proinflammatory mediators and further lung injury [ 50 ]. The early inflammatory exudative phase is followed by a fibroproliferative phase in which fibroblast and myofibroblast infiltrate and proliferate within the alveolar and interstitial spaces leading to lung fibrosis [ 51 ].

Oxidative stress is shown to mediate epithelial-endothelial barrier dysfunction and perpetuate inflammation in ARDS patients [ 52 , 53 ]. IPF is a progressive interstitial pulmonary fibrosis disorder with no known causal etiological factor. The lungs of patients with IPF show excessive deposition of matrix proteins such as fibronectin and collagen in the alveoli and lung parenchyma, which destroys the gas exchange surface leading to respiratory failure [ 54 ].

It is more prevalent in the USA and Europe than South America and South Asia. IPF disproportionately affects individuals above age 65 years, and often it is referred to as age-related disorder. Pathogenesis of IPF involves chronic insult to alveolar epithelial cells AEC , senescence of AEC and fibroblast, increased differentiation of fibroblast to myofibroblast [ 54 ] and increased accumulation of myofibroblast, which is mediated by oxidative injury, mitochondrial dysfunction, proteotoxicity and endoplasmic reticulum stress [ 14 , 55 ].

Emerging evidences implicate ROS by Nox4 as a key player in the pathogenesis of IPF [ 55 ]. Lipid peroxidation LPO in biological systems refers to the oxidation of cellular membrane lipids; and uncontrolled LPO is the most significant early biological process induced by oxidative stress state.

Excess LPO results in defective or dead cell, inactivation of critical proteins and activation of proinflammatory responses.

Together, these events not only initiate but also ensue disease progression. Numerous studies have overwhelmingly showed that LPO is a universal pathogenic event in all the respiratory diseases including COPD, IPF, ARDS and asthma [ 56 ].

Membrane lipids mainly glycerophospholipids PL esterified with polyunsaturated fatty acid PUFA and to a lesser extent free PUFA are the targets for oxidation. Free PUFAs released by action of phospholipases inside the cells are substrates for enzymes such as cyclooxygenase, lipoxygenase and cytochrome Ps, and hence, free PUFA undergoes enzyme-dependent peroxidation.

PL-PUFAs are predominantly oxidized by non-enzymatic process and highly depend on the radical species. The chemical reactions mediating the oxidation of PL-PUFA or free PUFA are similar; however, the products generated may vary.

LPO process involves three phases — initiation, propagation and termination. During the initiation phase, non-radical lipid molecule becomes a lipid radical. During termination process, antioxidant molecule, such as vitamin E, donates hydrogen, reduces lipid radicals without transforming itself into radical and thus terminates the LPO chain reaction.

Lipid hydroperoxides may further participate in additional oxidative reactions such as Fenton reaction catalysed by Fe or Cu, intra- and intermolecular oxidative modification and oxidative fragmentation. Finally, LPO produces diverse reactive aldehyde byproducts including widely studied malondialdehyde MDA and 4-hydroxynonenal 4HNE.

The oxidation of PL-PUFA also yields diverse species of oxidized phospholipids Ox-PLs aldehyde, alkene, peroxyl and alkane derivatives , which exhibit varying carbon chain length, hydrophobicity, reactivity, physical stability and biological activity [ 57 ].

The oxidized PUFA chain of glycerophospholipid may be released by the action of enzymes such as phospholipase A2 and PAF-acetyl hydrolases [ 57 ]. LPO products such as MDA, 4HNE and Ox-PLs produced in the lungs are not bystanders; rather they actively take part in the pathogenesis of lung disease by inducing cell death, epithelial-endothelial barrier dysfunction, inflammation and immune responses [ 58 ].

Ox-PLs and 4HNE are shown to mediate cytotoxicity through disruption of membrane integrity and activating cell death signalling programs such as apoptosis [ 59 , 60 ] and ferroptosis [ 61 , 62 ].

Ox-PLs generated following particulate matter exposure caused disruption of the endothelial barrier [ 62 ]. Ox-PLs are demonstrated to be dominant mediators of acute lung injury following gastric aspiration and viral infection [ 63 ]. Immunohistochemical analysis revealed greater accumulation of 4HNE in the airways, alveolar epithelium and inflammatory cells of the lungs of COPD patient when compared to smoker non-COPD patient with similar smoking history [ 67 ].

The bronchoalveolar lavage fluid from COPD patients shows higher levels of Ox-PLs when compared to healthy subjects [ 43 , 64 , 65 ]. The lung parenchyma of IPF patients showed greater accumulation of LPO products [ 54 , 55 , 68 ]. In most respiratory diseases, the levels of LPO byproducts increased with the severity of the pulmonary diseases, which suggest that the LPO is the central pathological event.

It is proven beyond doubt that oxidative stress is involved in the initiation, promotion and augmentation of inflammation by affecting multiple redox-sensitive signal transduction pathways, including Toll-like receptor TLR signalling, MAPK kinase signalling and inflammasome which ultimately leads to activation of proinflammatory transcription factors particularly nuclear factor kappa-light-chain-enhancer of activated B cells NF-κB and AP-1 [ 32 , 69 ].

TLR signalling is central in activating pulmonary inflammatory responses following infectious stress and oxidative stress [ 70 ]. During infection, TLRs recognize highly conserved microbial motifs referred to as pathogen-associated molecular pattern PAMP and activate downstream inflammatory signals [ 71 ].

In mammals, there are 13 TLRs, which are present either on the plasma membrane TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 or in endosome compartment TLR3, TLR7, TLR8, TLR9 inside the cell. Upon activation by PAMPs, TLRs undergo hetero- or homodimer and trigger a downstream signal transduction by recruiting adaptor molecules, myeloid differentiation factor 88 MYD88 or Toll-receptor-associated activator of interferon TRIF.

Except TLR3, a majority of TLRs recruit MYD88 that interacts with IRAK4 and phosphorylate IRAK1. Phosphorylated IRAK1 activates TNFR-associated factor 6 TRAF6 through phosphorylation, which subsequently stimulates protein kinase C and transforming growth factor TGF -β-activated kinase 1 TAK1.

TLR3 recruits adaptor molecule TRIF and activate TRAF3, which then activates TANK-binding kinase 1 TBK1. Activated TBK1 initiates interferon regulatory factor 3 to transcribe IFN-beta cytokine which by autocrine or paracrine mechanism elicits interferon signalling pathway activation.

Transcription factor NF-κB is a central node in regulating inflammation leading to the pathogenesis of COPD, asthma, ARDS and IPF. Only p65, Rel-B and C-Rel members have a transactivating domain. In an unstimulated cell, the NF-κB dimmer is sequestered in the cytoplasm by one of the three members of IκB protein complex consisting of IκBα, IκBβ and IκBε.

Activation of NF-κB may occur through canonical or noncanonical pathways. In canonical pathway, signals elicited by TLR s ligands, TNFα or IL-1β converge at IκK complex constituted of IκKα, IκKβ and IκKγ NEMO.

Upon activation IκK complex phosphorylates IκB on serine 32 and serine 36, which results in its proteasomal degradation and subsequently allows NF-κB to translocate into the nucleus.

Oxidative stress regulates activation of TLR signalling by multiple mechanisms [ 70 ]. NADPH oxidase-dependent ROS production is shown to enhance surface trafficking of TLR4 to lipid rafts, thereby augmenting downstream signals leading to hyperactivation of NF-κB [ 72 , 73 , 74 , 75 ].

Suppression of ROS generation by pharmacological NADPH oxidase inhibitor, genetic ablation of NADPH oxidase or exogenous antioxidants mitigated lipopolysaccharide LPS -induced TLR4 trafficking to lipid rafts and diminished downstream inflammatory responses [ 74 , 75 ].

Genetic ablation of NADPH oxidase dampened lung inflammation and injury in mice exposed to gram-negative bacteria, LPS, TNFα or bleomycin, suggesting a crucial impact of NADPH oxidase-elicited ROS in producing inflammation and associated tissue injury [ 55 , 74 , 76 , 77 , 78 ].

On the other hand, ROS derived from NADPH oxidase have also been involved in the resolution of lung inflammation [ 79 ]. Mitochondria-derived ROS also play a crucial role in enhancing TLR1, TLR2 and TLR4 signalling [ 80 ] and production of proinflammatory cytokines [ 81 ].

ROS is shown to augment TLR3 signalling partly by increasing the expression of TLR3 [ 82 ]. Oxidatively damaged biomolecules also act as danger-associated molecular patterns DAMPs and engage TLR4 to activate inflammatory responses.

For instance, oxidized phospholipids generated in lungs following exposures to chemicals, bacteria or virus act as DAMPs and activate TLR4 directed inflammatory responses [ 83 ], which is shown to play an essential role in the initiation of acute lung injury.

Often oxidative or nitrosative modification of proteins gives rise to modified proteins, which act as DAMPs and perpetuate inflammation. For example, protein adducts of 4HNE or MDA are shown to elicit inflammatory and immune responses [ 85 , 86 ] in the lungs.

S -nitrosylation of surfactant-D protein switches pulmonary surfactant protein-D from antioxidant to a proinflammatory mediator [ 87 ].

In early phases of oxidative stress, ROS may enhance NF-κB activation following exogenous stimuli; however sustained oxidative stress may repress NF-κB activation [ 88 ]. IκK complex, mainly IκKβ, is highly susceptible for redox modification.

Exposures to H 2 O 2 induced oxidative inactivation of IκKβ, which prevented phosphorylation of IκB protein and thus blocked TNFα-induced NF-κB activation [ 89 ].

In another study, H 2 O 2 posttreatment augmented IκK kinase activity in response to TNFα and leads to higher NF-κB activation [ 90 ]. H 2 O 2 treatment was also shown to enhance NF-κB activation in response to IL-1 cytokine by increasing NF-kappa B-inducing kinase activity [ 91 ].

IκKβ is also susceptible for S-nitrosylation, which inactivates IκKβ resulting in inhibition of NF-κB activation [ 92 ]. ROS and RNS are shown to directly modify NF-κB or its associated proteins and alter its transcriptional activity. ROS-dependent phosphorylation of serine on REL-A enhanced transcriptional activity of NF-κB [ 93 ].

S-nitrosylation of p65 subunit inhibited NF-κB activity. Kelleher et al. Excess ROS may also inactivate proteasome, which impedes IkB degradation and thus inhibits NF-κB activation [ 95 ].

Certain cellular redox proteins play an important role in modulating upstream pathways leading to NF-κB activation. In the nucleus, thioredoxin binds and protects oxidation of p65 subunit and enhances its DNA-binding activity. It is also shown that thioredoxin mediates denitrosylation of p65 following LPS exposure and facilitates NF-κB activation [ 94 ] in the lungs of mice.

Pretreatment with antioxidants such as N-acetylcysteine [ 96 ], GSH [ 97 , 98 ] or increased expression of antioxidant [ 72 , 97 , 98 ] attenuated lipopolysaccharide LPS -promoted NF-κB activation emphasizing the role of oxidative stress in regulating NF-κB activity.

Inflammasome is an intracellular multiprotein complex assembled in the cytoplasm, which recognizes microbial or environmental toxins and DAMPs e. ATP and activates inflammatory responses.

Several airborne environmental pollutants such as silica, ozone, particulate matter and tobacco smoke are shown to activate inflammasome, and therefore, inflammasome signalling is implicated in the pathogenesis of several lung disorders such as acute lung injury, pulmonary fibrosis, COPD and asthma [ 99 , ].

Activation of inflammasome produces active caspase-1 via autoproteolytic cleavage, which then mediates proteolytic cleavage of precursor pro-IL1β and pro-IL18 into biologically active cytokines. Among the inflammasome members, NLRP3 is redox sensitive, and therefore, intracellular ROS generated by NADPH oxidase or mitochondria have been shown to alter the activation of NLRP3 inflammasome [ ].

Ablation of NADPH oxidase or depletion of mitochondrial ROS inhibited ATP-induced caspase-1 activation and IL-1β secretion in macrophages [ , ]. ROS may also alter NLRP3 inflammasome activation by oxidizing redox-sensitive binding partners such as thioredoxin interaction protein TXNIP and mitochondrial antiviral sensing MAVS protein to NLRP3.

TXNIP is a negative regulator of thioredoxin. It is shown that ROS generated in response to a wide range of environmental stimuli oxidizes thioredoxin that liberates TXNIP. The liberated TXNIP interacts with NLRP3 and promotes NLRP3 activation [ ].

MAVS regulates type 1 interferon and NF-kB signalling following virus infection. It has been shown that ROS may induce MAVS aggregation [ ] on the outer membrane of mitochondria, which enables interaction with NLRP3 and promotes activation.

In macrophages and bronchial epithelial cells, LPS stimulation induces phosphorylation of p38 MAPK and mediates the generation of numerous proinflammatory cytokines such as TNFα, IL-6, IL-1β [ ] and also T cell Th1 and Th17 -polarizing cytokines such as IFNγ, IL and IL [ ]. In cigarette smoke-exposed mouse models, specific activation of p38 MAPK is shown to be a determinant of susceptibility to emphysema [ ].

Exposure of cells to H 2 O 2 induces phosphorylation of p38, ERK and JNK [ ]. Although precisely how ROS activates MAPK kinase is less understood, it is postulated that ROS mediates oxidative inactivation of protein tyrosine phosphatases and MAPK phosphatases, which inactivate MAPK kinase by dephosphorylating [ , ].

Because MAPK kinase plays a pivotal role in regulating inflammation, kinase inhibitors, particularly p38 MAPK inhibitors, are shown to be promising drug for treatment of airway disorders such as COPD and asthma [ ]. Apoptosis a programmed cell death is involved in removing damaged, infected and potentially neoplastic cells, and increased apoptotic cell death is involved in the pathogenesis of several lung disorders.

Apoptosis can be activated by several factors including receptor-mediated signals and DNA damage; however, in most cases, ROS functions as an upstream activator of apoptosis. Apoptosis is mediated by extrinsic and intrinsic pathways [ 40 , , ]. Oxidative stress may induce these processes by activating several signalling pathways, including MAPK ERK, JNK and p38 , cell-cycle regulators, protein kinase B and caspases [ ].

Further, 4HNE can directly interact with death ligand Fas on the cell membrane and activate apoptotic process [ ]. Finally, 4HNE alters cytosolic calcium homoeostasis and mitochondrial calcium uptake, resulting in apoptosis [ ].

Several studies have reported oxidative stress-dependent apoptosis in pulmonary fibrosis, obstructive airway diseases and ARDS [ 12 , 40 , 41 , 44 , , ]. Mitochondria may also sense external stressors and alter its function to mount a protective adaptive stress response program [ ]. However, prolonged exposures to environmental toxicants induce mitochondrial dysfunction mainly via oxidative stress mechanisms [ ].

Mitochondrial dysfunction may present in the form of increased mitochondrial ROS, diminished oxidative phosphorylation, increased mitochondrial mass, secretion of mitochondrial DAMPs, mitochondrial DNA damage, decreased mitochondrial biogenesis and increased accumulation of defective mitochondria [ 13 , , ].

Several studies suggest that mitochondrial dysfunction is a predominant pathological feature in all lung diseases [ 13 , , ].

In lungs, owing to their dynamic function, alveolar type II epithelial cells, bronchial ciliated epithelial cells, vascular smooth muscle cells and macrophages are richer in mitochondria than other lung cell types. In normal conditions, lung cells preferentially use glucose end product, pyruvate, for oxidative phosphorylation.

However, during stressful physiological or pathological conditions such as increased surfactant production , alveolar type II epithelial cells rely on fatty acids for energy demand.

Under chronic stress conditions, mitochondrial bioenergetic metabolic function may get altered in lung cells. For example, cigarette smoke exposure is shown to damage mitochondrial structure and affect oxidative phosphorylation in lung cells [ ]. Likewise, primary bronchial epithelial cells from severe COPD patients showed accumulation of abnormal mitochondria [ ].

Airway smooth muscles and diaphragmatic and external intercoastal muscle of patients with COPD are associated with altered mitochondrial oxidative phosphorylation [ ]. Bronchial epithelium in asthmatics is associated with reduced mitochondrial oxidative phosphorylation and decreased expression and activity of cytochrome c oxidase [ , , ].

To meet the energy demand and mount stress response, chronic stress may also induce mitochondrial biogenesis in lung cells. Alveolar type II epithelial cells showed increased mitochondrial biogenesis during acute lung injury, pneumonia and hyperoxia-induced lung injury [ ].

Bronchial smooth muscles of asthmatic airways are associated with increased mitochondrial biogenesis, and this was linked to higher expression of nuclear respiratory factor 1, peroxisome proliferator-activated receptor γ coactivator PGC -1α and mitochondrial transcription factor A [ ].

Abnormal or defective mitochondria in the cells are constantly removed by a process called mitophagy, which is regulated by PTEN-induced kinase 1 PINK1. Expression of PINK1 is negligible in healthy mitochondria; however its levels increase on the outer mitochondrial membrane of defective mitochondria, which recruits parkin and autophagy proteins and facilitates mitophagy.

Impaired mitophagy leads to accumulation of damaged mitochondria in the cells, which promotes cellular senescence [ , ]. Increased cellular senescence has been observed in the lungs of COPD and IPF patients [ , , ].

Exposures to cigarette smoke in lung cells are shown to inhibit mitophagy, increase accumulation of damaged mitochondria [ , , ] and induce cellular senescence.

Alveolar type II cells of IPF patients are associated with abnormal mitochondria due to diminished PINK1 expression [ ]. In mouse models, PINK1 knockdown impaired mitophagy and increased accumulation of defective mitochondria and promoted fibrosis in aging lungs [ ].

On contrary, increased mitophagy may also contribute to pathogenesis of lung diseases. For example, Staphylococcus aureus infection increased mitochondrial expression of PINK1 and mediated acute lung injury, which was ablated in PINK1 knockout mice [ ].

Mitochondrial dysfunction may also lead to leakage of cytochrome c, which triggers programmed cell death [ , ]. Mitochondria have been shown to regulate various forms of cell death such as extrinsic apoptosis, intrinsic apoptosis, necroptosis and pyroptosis [ ], and all these forms of cell death have been reported in various lung diseases including COPD, asthma and IPF.

At physiological concentrations, many mitochondrial-derived molecules including ROS help in normal cellular signalling. However, when secreted in excess, mitochondrial-derived molecules act as mitochondrial DAMPs mtDAMPs and contribute to lung injury. Mitochondrial DNA mtDNA , a well-studied mtDAMP, is released by damaged mitochondria, which is shown to engage TLR9 and inflammasome to initiate inflammatory responses in lung cells [ , ].

Circulatory levels of mtDNA correlate well with severity and mortality in sepsis and ARDS patients [ ]. Excess ATP released in the lungs by dead or damaged cells also acts as mtDAMPs and activates inflammatory response via NLRP3 inflammasome [ , ].

Elevated levels of ATP are reported in bronchoalveolar lavage fluid of patients with COPD [ ] and asthma as well as in mouse models of asthma [ ] and pulmonary fibrosis [ ]. Other mtDAMPs such as TFAM and N-formyl peptide are also implicated in driving inflammatory responses in lungs [ ].

Cardiolipin, a predominant lipid located in mitochondrial inner membrane, is released by damaged mitochondria and acts as mtDAMP. Levels of cardiolipin increase during lung injury and are shown to mediate cell death and activate inflammasome signals [ , ].

Additionally, cardiolipin in lung fluid was shown to inhibit surfactant activity and worsen lung function in mouse models of pneumonia [ ]. Finally, mitochondrial-derived ROS plays diverse roles in the pathogenesis of lung diseases including perpetuating oxidative stress, augmenting TLR-NF-κB signalling and cell death [ 13 , 81 , , , , , ].

The endoplasmic reticulum ER is involved in protein biosynthesis and post-translational modifications and perturbation of ER homeostasis results in ER stress which affects both these process. To overcome the ER stress, cells initiate an evolutionarily conserved mechanism called unfolded protein response UPR.

Activation of UPR leads to decrease in protein synthesis by selectively inhibiting translation, increases protein folding machinery and removes misfolded proteins through endoplasmic reticulum-associated degradation ERAD pathway [ ]. If UPR fails to alleviate ER stress, it activates apoptotic signalling mechanism [ ] and, thus, helps in removal of damaged or stressed cells.

Chronic ER stress is pathological and is associated in the pathogenesis of many lung disorders. Markers of ER stress are elevated in neutrophil-associated steroid-resistant asthma [ ].

In COPD model, cigarette smoke exposure elicited ER stress and apoptosis [ , ]. ER stress was found to be elevated in lungs of human IPF and murine models of pulmonary fibrosis [ ]. ER stress is also reported to be involved in the hyperoxia-induced acute lung injury in neonates [ ].

Sustained oxidative stress milieu may promote ER stress by increasing cellular stress and decreasing the efficiency of protein folding pathways [ ]. A relationship has been established between ROS generation and activation of ER stress response [ ]. NADPH oxidase s and mitochondria are reported as a probable ROS source during ER stress.

Chronic oxidative stress state may disturb the epigenetic state of the cell by multiple mechanisms. For example, superoxide radicals can directly mediate transfer of a methyl group from SAM to a cytosine residue without the need of DNMT by deprotonating C5 [ ]. ROS may increase DNMT expression and indirectly affect DNA methylation [ ].

On the other side, ROS and RNS are reported to modulate the activity of HDACs histone deacetylase that may influence the expression of target genes by removing acetyl groups [ , , , ] on histones.

Recently, various ncRNAs, in particular microRNAs miRNAs , are regulated by ROS. Interestingly, some miRNAs such as miR-9, miR, miR and miR are shown to control cellular ROS levels and are termed as redoximiRs [ ].

ROS are also shown to interfere with miRNA biogenesis process as well as miRNA maturation by modulating Dicer and argonaute RISC catalytic component [ ].

In the context of the lung, several lines of evidence support that ROS-dependent changes in the epigenetic background play an important role in the pathogenesis of respiratory diseases. For instance, cigarette smoke exposures inhibit HDAC2 enzyme activity through oxidative and nitrosative modification, which leads to enhanced inflammatory responses, senescence and steroid resistance in COPD [ , ].

Another study shows that Sirtuin 1 promotes lung epithelial cell death following hyperoxia by selectively deacetylating the transcription factor nuclear factor erythroid-derived 2 -like 2 NRF2 , accompanied by reduced levels of antioxidant enzymes [ ].

In case of asthma, one study reported that exposure to environmental particulate matter could lead to demethylation of iNOS gene; subsequently this may lead to increased expression of proinflammatory iNOS, leading to lung inflammation [ ]. The involvement of many factors including ROS in epigenetics of IPF has been reviewed [ ].

Fibrotic lungs are associated with increased oxidative stress, as indicated by the elevated levels of biomarkers of lipid, protein and DNA damage, and several reports have implicated ROS in profibrotic processes.

During the inflammatory phase of fibrosis, ROS along with growth factors TGF-β, PDGF and CTGF and cytokines IL-6 and IL stimulate fibroblast to produce ECM.

Among these, TGF-β is the most dynamic pro-fibrogenic cytokine, which regulates important biological processes such as EMT, fibroblast activation and differentiation and ECM production [ ]. ROS may influence the transformation of latent TGF-β complex into its active form, which then binds to its receptors and activates signalling pathways such as SMAD-dependent or SMAD-independent e.

MAPK and PI3K pathways and enhances the transcriptional activity of various profibrotic genes such as α-SMA and COL1 [ ]. On the other hand, elevated TGF-β itself reciprocally induces the production of NOX4-dependent ROS [ ].

NOX4 is selectively upregulated in the lungs of IPF patients and is associated with the endothelial cell dysfunction and hypoxia [ 14 , 55 ]. Elevated NOX4-generated ROS triggers DNA oxidation and activates other ROS-dependent signalling pathways such as JNK and NF-κB [ ]. Silencing of NOX4 by siRNA inhibited TGF-β-mediated profibrotic responses in the lungs of mice [ 55 ].

Further, NOX4 knockout mice and use of NOX4 inhibitor in mice protected against bleomycin-induced acute lung injury and the onset of fibrosis [ 76 , ]. In fibroblasts, mitochondrial ROS has been shown to induce the expression of profibrotic genes during fibroblast differentiation [ ].

ROS may also modulate integrins, transmembrane receptors that activate FAK, which in turn activate rac1 protein and initiate production of collagen and other profibrotic actors CTGF and α-SMA [ ]. ROS and RNS may modulate activity of matrix metalloproteinases MMPs through the inhibition of cysteine switch and thus influence ECM degradation.

ROS are also shown to induce epithelial cell senescence that may result in a diminished capacity for regeneration of epithelium [ ].

In IPF, epithelial damage and epithelial cell senescence in the lung are interconnected with increased mitochondrial ROS production.

Similarly, in IPF fibroblasts, ROS generation is reported to require for the maintenance and differentiation [ ]. Furthermore, oxidative stress may cause ER stress, which facilitates fibrogenesis through activation of EMT, pro-apoptotic pathways and inflammatory responses [ ].

In summary, oxidative stress can alter different cellular processes that amplify fibrotic responses. A thin layer of gelatinous mucus covers the apical epithelial surfaces of mammalian respiratory tract, which forms a protective barrier against airborne microbes and toxins, but conversely, excessive mucus production becomes pathologic in muco-obstructive airway diseases [ ].

Mucus is secreted by goblet cells in the airway epithelium and is mainly composed of mucin, which is a large filamentous glycoprotein [ ].

Mucus is also rich in antioxidant scavengers such as glutathione, uric acid and ascorbic acid. Chronic airway inflammatory diseases such as chronic bronchitis and asthma are characterized by mucus hypersecretion [ ], and ROS hydroxyl radicals, superoxide anions and hydrogen peroxides are key regulators of mucus production in goblet cells via transcriptional regulation of mucin genes [ ].

Of 12 mucin genes, MUC5AC is a major inducible mucin gene in airways and reported to be highly expressed in muco-obstructive airway disorders [ , ]. Yu et al. Likewise, activation of other pathways, such as NF-κB, is also linked to ROS-mediated MUC5AC production in airways.

However, the majority of the studies suggest that EGFR is involved in ROS-mediated mucus hypersecretion [ , , ]. The lungs are exceptionally exposed to greater oxidative environment than other organs. The inhaled toxicants are by themselves oxidants or may induce oxidative stress inside lung cells.

To protect from the inhaled environmental oxidants, lungs are endowed with efficient antioxidant defences that includes both non-enzymatic and enzymatic antioxidant defences.

The airways are covered with respiratory tract epithelial lining fluid RTLF which forms a physical barrier between the external environment and underlying respiratory tract epithelial cell layer. The respiratory tract lining fluid traps most of the inhaled toxicants, and by the help of mucociliary action, these trapped toxicants are cleared from the lungs.

The respiratory tract lining fluid is rich in many non-enzymatic low-molecular-weight antioxidant scavengers, which directly interact and detoxify the inhaled oxidants and thereby prevent the direct contact of inhaled toxicants with the underlying epithelium.

The major antioxidant molecules in the RTLF are GSH, ascorbic acid, uric acid and vitamin E Fig. Additionally, airway epithelial cells secrete certain antioxidant proteins into RTLF, which also function as antioxidant scavengers.

Glutathione, a thiol-tripeptide comprised of glutamate, cysteine and glycine, is the most important antioxidant in RTLF, and its levels in RTLF are close to times more than in the plasma [ ]. GSH scavenges a number of ROS products including hydroxyl, H 2 O 2 , hypochlorous acid and lipid peroxyl radical generated during exposures to inhaled oxidants such as cigarette smoke, ozone and allergens, and therefore, reduced bronchoalveolar lavage GSH levels has been a hallmark feature of many pulmonary diseases including COPD, asthma, ARDS and IPF [ ].

Besides scavenging ROS, GSH is a co-substrate for the enzyme glutathione peroxidase and glutathione S-transferase which mediate detoxification of lipid hydroperoxides and xenobiotics, respectively. GSH in RTLF also protects secretory antiproteases such as alphaantitrypsin, alphamacroglobulin and secretory leukoprotease inhibitor from oxidative inactivation [ ].

Therefore, a lower level of tissue GSH intensifies oxidant-induced lung inflammatory injury. GSH also maintains thiol status of extra- and intracellular proteins and facilitates post-translational modification of proteins such as S-glutathionylation.

Protein S-glutathionylation may alter the function of many intracellular proteins. For example, S-glutathionylation inhibits DNA-binding activity of p65 or p50 subunits [ ], and S-glutathionylation inactivates IκKβ [ ] resulting in diminished NF-κB activity.

Ascorbic acid is another major antioxidant in RTLF. It directly reduces the oxidative potential of oxidants present in tobacco smoke [ ] or particulate matter [ ] as well as inhibits ROS generation by NADPH oxidase activity [ ].

Besides reducing the inhaled oxidants, ascorbic acid also reduces oxidized antioxidants in RTLF such as vitamin E, thereby maintaining the total antioxidant capacity of the lungs during oxidative insult. Ascorbic acid is rapidly used in RTLF fluid upon exposures to environmental oxidants including ozone, nitrogen dioxide, particulate matter and tobacco smoke [ , , ] as indicated by the depletion of ascorbic acid levels.

Supplementation of ascorbic acid protected from cigarette smoke-induced emphysema by inhibiting protein oxidation in mouse models [ ] highlighting the antioxidant potential of ascorbic acid in the lungs.

Asthmatics are associated with lower levels of ascorbic acid [ , ], and the beneficial effect of supplementation of ascorbic acid in asthmatics has been mixed and inconclusive [ ]. Ascorbic acid has been shown to attenuate acute lung injury caused by inhalation of oxidant chlorine gas [ ].

Ascorbic acid may also take part in pro-oxidant activity in the presence of free iron by taking part in Fenton reaction. Uric acid formed due to purine metabolism is one of the major water-soluble scavengers of singlet oxygen, ozone and peroxylnitrite ONOO in RTLF [ ].

Uric acid has been shown to be a major antioxidant in nasal secretion [ ] and RTLF and helps in the removal of inhaled ozone and neutralizes the oxidative potential of inhaled particulate matter in humans [ ]. Uric acid also reacts and neutralizes gaseous free radical nitrogen dioxide [ , ].

The antioxidant scavenging activity of uric acid greatly depends on ascorbic acid and hydrophilic environment. Uric acid reacts with radical species and forms urate free radical which is then quenched by ascorbic acid.

In lipophilic environment, uric acid fails to stop the self-propagating lipid peroxidation reaction. Subnormal levels of serum uric acid were associated with greater risk for COPD and greater morbidity, including reduced 6-minute walk test and greater burden of exacerbations [ , ].

Vitamin E tocopherol is a lipophilic antioxidant scavenger in RTLF which neutralizes ROS and attenuates self-propagating lipid peroxidation reactions in the airways. Patients with asthma and COPD are associated with lower serum levels of vitamin E [ ] as compared to healthy subjects, and this formed the basis for vitamin E supplementation trials to prevent respiratory diseases.

Vitamin E trials reduced levels of markers of oxidative damage in smokers [ ]. Dietary intake of vitamin E improved lung function in healthy aging population [ ]. Vitamin E supplements reduced endotoxin-induced sputum eosinophilia in asthma patients [ ].

In experimental mouse models, administration of vitamin E isoform γ-tocotrienol protected from cigarette smoke-induced emphysema [ ] and dust mite-induced asthma. However, supplementation of vitamin E showed no benefits in the management or treatment of asthmatics [ ].

The surfactant proteins included high-molecular-weight hydrophilic surfactant proteins A and D and low-molecular-weight hydrophobic surfactant proteins B and C. Unsaturated phospholipids and surfactant protein are prone for oxidative inactivation following exposures to environmental oxidants such as ozone.

Both surfactant proteins A and D exhibited direct antioxidant activity and protected phospholipids and LDL from copper or ferric chloride-induced oxidation [ ].

Surfactant proteins A and D also protected macrophages from hydroperoxide-induced cell death [ ]. Clara cell CC16 protein secreted by clara cells also exhibits antioxidant and anti-inflammatory activity [ ]. Mice with genetic disruption of CC16 showed elevated oxidative damage and structural injury following exposure to cigarette smoke [ ].

Low circulating levels of CC16 are shown to be associated with poor lung function growth in children [ ] and smoking-dependent lung function decline in adults [ ] as well as patients with COPD and asthma [ ].

Lungs are endowed with robust antioxidant protein defences to minimize oxidative stress caused by airborne environmental toxicants.

Major pulmonary antioxidant enzymes include superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, hemeoxygenase-1, peroxiredoxin-1, thioredoxin and thioredoxin reductase [ 40 , 41 , , ]. Exposures to environmental oxidants such as cigarette smoke lead to the coordinated activation of all these antioxidant proteins [ 39 , 40 , 41 ] as illustrated in Fig.

The importance of individual antioxidant enzyme has been exemplified using knockout and transgenic mouse models. The importance of each of the SOD isoforms in protecting lungs from oxidants has been well studied. EC-SOD prevented fibrosis in lungs by inhibiting oxidative degradation of the matrix proteins, type I and type IV collagen [ ].

Cigarette smoke exposure and elastase instillation caused greater emphysema in EC-SOD-deficient mice; however transgenic EC-SOD mice were protected from emphysema [ ].

Overexpression of Mn-SOD has also been reported in alveolar macrophages during sarcoidosis and in the lung tissue of IPF patients [ ]. SOD is highly sensitive for oxidative inactivation, and therefore, SOD levels are depleted in disease lungs. In IPF, there was no expression of EC-SOD in fibrotic areas where there is an enhancement of oxidative burst [ ].

Enzyme activity of SOD was significantly low in asthmatics as compared to healthy subjects, which is further depleted during asthma attack [ , ].

Oxidative and nitrosative modification of Mn-SOD was observed in the airways of asthmatic, which correlated with asthma severity [ ]. Therefore, increasing SOD levels in the lungs by pharmacological approaches including SOD mimetics are thought to be a promising approach for mitigating pathogenesis of pulmonary disorders.

Glutathione peroxidase GPx detoxifies hydrogen peroxide and reactive lipid hydroperoxides using GSH as an electron donor. In mammalian lungs, four major selenium-containing GPx isoforms are expressed — GPX1 classical GPx , GPX2 gastrointestinal GPx , GPX3 extracellular GPx and GPX4 phospholipid GPx.

Bronchial epithelial cells and alveolar macrophages produce Gpx3 in epithelial lining fluid, which detoxify lipid hydroperoxides generated in RTLF. GPx2 is a predominant glutathione peroxidase expressed in the lungs following cigarette smoke exposure and silencing GPx2 by RNA interference enhanced cytotoxicity in bronchial epithelial cells following treatment with cigarette smoke extract [ 42 ].

In comparison with wild type, GPx2-deficient mice showed greater levels of oxidative damage, airway inflammation and airway hyperresponsiveness in ovalbumin-induced asthma mouse model [ ].

Basal levels of GPx in lungs were shown to be a key determinant of severity of pulmonary fibrosis in mouse models [ ]. Peroxiredoxins are the family of peroxidase enzymes, which play a dominant role in detoxification of hydrogen peroxide within the cells.

Human lung expresses all the six members of a peroxiredoxin family [ ]. Thioredoxin reductase is a selenium-containing flavoprotein oxidoreductase enzyme expressed in mammalian lungs, which primarily catalyses NADPH-dependent reduction of thioredoxin, an important redox protein involved in transcriptional regulation of NF-κB [ 94 ].

Heme oxygenase-1 HO-1 is a highly inducible protein in the lungs which exhibits anti-apoptotic, anti-inflammatory and antioxidant activities. HO-1 catalyses heme to carbon monoxide and biliverdin and the latter is converted to bilirubin. Although the mechanism by which HO-1 mediates antioxidant and anti-inflammatory activity is less understood, the end byproducts of HO-1 enzyme activity, CO, bilirubin and Fe are shown to mediate the beneficial effects [ ].

HO-1 knockout mice display greater inflammation, apoptosis and tissue injury following an ischemic reperfusion injury [ ], while lung-specific expression mitigated LPS- and hyperoxia-induced lung inflammation [ , ].

Many lines of evidence show that transcription factor Nrf2 is a central regulator of nearly all cellular antioxidant proteins in the lungs and other organs [ ]. In a normal cell, Nrf2 is held in the cytoplasm by a cysteine-rich, redox sensor Keap1 protein, which functions as an adaptor molecule and bridges Nrf2 with Cul3-based E3 ubiquitin ligase [ , ].

Under normal condition, Keap1-Cul3-based E3 ubiquitin ligase ubiquitinates Nrf2 and directs it to proteasomal degradation. However, upon exposure to ROS and electrophiles, Keap1 protein undergoes conformational change due to oxidative modification of its cysteine residues, which disrupts the interaction of Nrf2 with Cul3-dependent E3 ligase and prevents Nrf2 ubiquitination.

Genetic disruption of Nrf2 ablates transcriptional induction of antioxidant genes in the lungs and sensitizes the mice to several environmental lung diseases such as cigarette smoke-induced emphysema [ 41 ], allergen-induced asthma [ ], LPS-induced acute lung injury [ 97 ] and bleomycin-induced pulmonary fibrosis [ ] and sepsis [ 72 , 74 , ].

In contrast, activation of Nrf2 by pharmacological activators and genetic disruption of Keap1 protected mice from development of these pulmonary diseases [ ]. Nrf2-regulated antioxidant has been shown to be downregulated in lungs of patients with COPD [ ] and IPF [ ], underscoring the importance of Nrf2 pathway in protecting the lungs from oxidative stress.

Besides Nrf2, NF-κB and AP-1 also regulate transcriptional expression of certain antioxidant genes in the lungs [ 88 , ]. Despite the compelling evidence from preclinical and clinical studies that pulmonary antioxidants play a pivotal role in protecting from environmental pulmonary diseases, clinical trials testing antioxidant therapy have shown modest to no significant beneficial effects.

Clinical trials with N-acetyl-L-cysteine NAC supplementation have shown mixed results. Meta-analysis of all clinical trials using oral NAC concluded that long-term intake of NAC may reduce the acute exacerbations of chronic bronchitis [ ].

However, more recent randomized double-blinded multicentre clinical trial of oral NAC reported no beneficial effect in the prevention of lung function decline and COPD exacerbation [ ]. Vitamin C and E clinical trials showed no improvement on lung function decline in COPD patients [ ].

Supplementation of Nrf2 activator, sulforaphane, in the form of broccoli sprout homogenates reduced bronchoconstrictor hyperresponsiveness in asthmatics [ ]. In a randomized clinical trial, supplementation of sulforaphane showed no significant upregulation of Nrf2-regulated antioxidants in lungs of COPD patients [ ].

In another study, consumption of broccoli sprout showed no effect on eosinophilic inflammation as well as markers of oxidative stress in atopic asthmatic patients [ ]. In smokers, consumption of broccoli sprout homogenates reduced influenza virus-induced inflammation [ ]. Consumption of broccoli tea has been reported to promote rapid and sustain detoxification of air pollutants in a randomized clinical trial in China [ ].

The reasons for lack of consistent benefits of antioxidant trials for pulmonary disease are still puzzling. Perhaps it could be combination of poor efficacy of a single antioxidant agent as well as limited bioavailability.

Oxidative stress is a central hallmark pathological feature of all the respiratory disease. Oxidative stress elicits both reversible and irreversible macromolecule damage oxidative modification of lipids, proteins and DNA.

As illustrated in Fig. Experimental evidences suggest that antioxidant therapy may prevent or mitigate oxidative stress-mediated macromolecular damage and abnormal signal transductions and, thereby, protect from development and progression of disease. However so far, most antioxidant clinical trials have shown poor efficacy to mitigate disease progression, which may be attributed to insufficient bioavailability of antioxidant agent in the lungs and also inability to reverse pathogenic events such as epigenetic changes, macromolecule damage and mitochondrial dysfunction.

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As no truly effective therapies exist for lung cancer, disprders oxidative stress and respiratory disorders and chronic obstructive respiratoty disease COPD Replenish natural beauty, at present, it respirtaory important to comprehensively strss the relationship between oxidative stress and respieatory diseases to identify truly oxiddative therapeutics. Since there qnd no quantitative and qualitative bibliometric analysis Maximizing Performance through Nutrition the literature in diworders area, oxidativf oxidative stress and respiratory disorders provides an in-depth analysis of publications related to oxidative stress and pulmonary diseases over four periods, including from tototoand to Interest in many pulmonary diseases has increased, and the mechanisms and therapeutic drugs for pulmonary diseases have been well analyzed. Lung injury, lung cancer, asthma, COPD and pneumonia are the 5 most studied pulmonary diseases related to oxidative stress. Inflammation, apoptosis, nuclear factor erythroid 2 like 2 NRF2mitochondria, and nuclear factor-κB NF-κB are rapidly becoming the most commonly used top keywords. The top thirty medicines most studied for treating different pulmonary diseases were summarized. Oxidative stress is an upstream event leading to multiple diseases, including cancer, cardiovascular diseases, neuron degenerative diseases and pulmonary diseases Klaunig, ; van der Vliet et al. Dizorders, respiratory diseases are oxidative stress and respiratory disorders cause of disability and mortality, and more alarmingly, it disproportionately anf developing countries, which is largely attributed oxidative stress and respiratory disorders oxidatibe oxidative stress and respiratory disorders of air. Tobacco oxidaitve and emissions from combustion of stress fuel and biomass ooxidative are Vitamin-packed weight loss pills major airborne pollutants affecting human lung health. Oxidative stress is the dominant driving force by which oxxidative airborne pollutants exert their toxicity in lungs and cause respiratory diseases. Most airborne pollutants are associated with intrinsic oxidative potential and, additionally, stimulate endogenous production of reactive oxygen species ROS and reactive nitrogen species RNS. Elevated ROS and RNS in lungs modulate redox signals and cause irreversible damage to critical biomolecules lipids, proteins and DNA and initiate various pathogenic cellular process. This chapter provides an insight into oxidative stress-linked pathogenic cellular process such as lipid peroxidation, inflammation, cell death, mitochondrial dysfunction, endoplasmic reticulum stress, epigenetic changes, profibrotic signals and mucus hypersecretion, which drive the development and progression of lung diseases. Lungs are associated with robust enzymatic and non-enzymatic GSH, ascorbic acid, uric acid, vitamin E antioxidant defences.

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