Review
Oxidant and antioxidant balance in the airways and airway diseases

https://doi.org/10.1016/j.ejphar.2005.12.087Get rights and content

Abstract

Although oxygen is a prerequisite to life, at concentrations beyond the physiological limits it may be hazardous to the cells. Since the lungs are directly exposed to very high amounts of oxygen, it is imperative for the organ to possess defences against possible oxidative challenge. The lungs are therefore endowed with an armamentarium of a battery of endogenous agents called antioxidants. The antioxidant species help the lungs ward off the deleterious consequences of a wide variety of oxidants/reactive oxygen species such as superoxide anion, hydroxyl radical, hypohalite radical, hydrogen peroxide and reactive nitrogen species such as nitric oxide, peroxynitrite, nitrite produced endogenously and sometimes accessed through exposure to the environment. The major non-enzymatic antioxidants of the lungs are glutathione, vitamins C and E, beta-carotene, uric acid and the enzymatic antioxidants are superoxide dismutases, catalase and peroxidases. These antioxidants are the first lines of defence against the oxidants and usually act at a gross level. Recent insights into cellular redox chemistry have revealed the presence of certain specialized proteins such as peroxiredoxins, thioredoxins, glutaredoxins, heme oxygenases and reductases, which are involved in cellular adaptation and protection against an oxidative assault. These molecules usually exert their action at a more subtle level of cellular signaling processes. Aberrations in oxidant: antioxidant balance can lead to a variety of airway diseases, such as asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis which is the topic of discussion in this review.

Introduction

The lung is the only organ in the entire human architecture, which has the highest exposure to atmospheric oxygen. Owing to its large surface area and blood supply, the lung is susceptible to oxidative injury by virtue of myriads of reactive forms of oxygen species and free radicals. Reactive oxygen species and reactive nitrogen species are highly unstable due to unpaired electrons that are capable of initiating oxidation. As a part of their normal physiology and external challenges posed by various microorganisms and chemicals, biological systems continuously generate reactive oxygen/nitrogen species to ward off these agents and in turn are exposed to the deleterious effects of these reactive species. Free radical species may be endogenously produced by metabolic reactions (e.g. from mitochondrial electron transport during respiration or during activation of phagocytes) or exogenously, such as air pollutants or cigarette smoke.

In situ lung injury due to reactive oxygen species is linked to oxidation of proteins, DNA, and lipids. These oxidized biomolecules may also induce a variety of cellular responses through the generation of secondary metabolic reactive species. Physiologically, reactive oxygen/nitrogen species inflict their effects by remodeling of extracellular matrix and blood vessels, stimulate mucus secretion and alveolar repair responses. Previous review has highlighted the importance of reactive oxygen/nitrogen species in airway inflammation (Folkerts et al., 2001). On the biochemical level, reactive oxygen/nitrogen species inactivate antiproteases, induce apoptosis, regulate cell proliferation and modulate the immune system in the lungs (Rahman and MacNee, 1996, Rahman and MacNee, 1999). At the molecular level, increased reactive oxygen/nitrogen species levels have been implicated in initiating inflammatory responses in the lungs through the activation of transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1, signal transduction, chromatin remodeling and gene expression of pro-inflammatory mediators (Rahman and MacNee, 1998). The lungs are endowed with an armamentarium of a battery of endogenous agents called antioxidants. The major non-enzymatic antioxidants of the lungs are glutathione (GSH), vitamins C and E, beta-carotene, uric acid and the enzymatic antioxidants are superoxide dismutases (SODs), catalase and peroxidases. These antioxidants are the first lines of defence against the oxidants and usually act at a gross level. Recent insights into cellular redox chemistry have revealed the presence of certain specialized proteins such as peroxiredoxins, thioredoxins, glutaredoxins, heme oxygenases and reductases, which are involved in cellular adaptation and protection against an oxidative assault. These molecules usually exert their action at a more subtle level of cellular signaling processes. Aberrations in oxidant and antioxidant balance can lead to a variety of respiratory diseases, such as asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.

This article will discuss the various oxidants and antioxidant systems of the airways emphasizing their role in the respiratory tract physiology and their implications in chronic respiratory diseases.

Section snippets

Cell-derived reactive oxygen species/oxidants

The lung is vulnerable to oxidant damage because of its location, anatomy and function (Crystal, 1991). Lung epithelium is constantly exposed to oxidants generated internally as a part of normal metabolism, as well as to oxidants in the ambient air, including ozone, nitrogen dioxide, diesel exhaust and cigarette smoke (Fig. 1).

A free radical is any species capable of independent existence that contains one or more unpaired electrons (Halliwell, 1991, Halliwell, 1994). The most important

Overview of oxidants in lung diseases

Increased oxygen burden in the lungs may arise due to accumulation of inflammatory cells in the lower respiratory tract, including macrophages and neutrophils. These cells show an exaggerated generation of O2•− and OH in patients with acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and pneumoconiosis (Crystal, 1991, Rahman and MacNee, 1996, Wallaert et al., 1990). Free radical reactions have been suggested to play a contributory

Non-enzymatic antioxidants of lungs

These are low molecular weight compounds such as vitamins (vitamins C and E) (McFadden et al., 2005, Finglas et al., 1993) beta carotene (Rock et al., 1993, Krinsky and Deneke, 1982), uric acid, glutathione, a tripeptide (l-γ-glutamyl-l-cysteinyl-l-glycine) which comprises of a thiol (sulfhydryl) group (Eiserich et al., 1995, Cantin et al., 1987a, Cantin et al., 1987b, Heffner and Repine, 1989, Comhair and Erzurum, 2002, Rahman and MacNee, 1999) (Table 1).

Enzymic lung Antioxidants

The major enzymic antioxidants of the

Superoxide dismutase

Superoxide dismutase is present in essentially every cell in the body and has been shown to play an important role in protecting cells and tissues against oxidative stress. Three types of SODs have been reported (see below). All the forms of SODs act by a common mechanism of dismutation of superoxide anion (Fig. 2) to a less potent hydrogen peroxide as shown in the following equation:2O2•− + 2H+ + SOD  H2O2 + O2

The reaction is pseudo first order and almost diffusion limited (Michaelis-Menten constant > 

Catalase

This antioxidant enzyme is a homotetrameric protein (MWt., 240 kDa) (Fridovich and Freeman, 1986) and decomposes hydrogen peroxide into water and oxygen as shown in the equation:2H2O2  2H2O + O2

Catalase is ubiquitous to most aerobic cells in animals and is especially concentrated in the liver and erythrocytes. The brain, heart, skeletal muscle contains only low amounts. Catalase is found in peroxisomes and in the cytoplasm and is specially localized in the alveolar type II pneumocytes and

Glutathione peroxidase

Glutathione peroxidases are a family of selenium dependent and independent antioxidant enzymes and can be divided into two groups, cellular and extracellular.

In general glutathione peroxidase is a tetrameric protein (MWt, 85 kDa). It requires 4 atoms of selenium bound as seleno-cysteine moieties that confer the catalytic activity. Glutathione peroxidase reduces hydrogen peroxide to H2O by oxidizing glutathione as shown in Eq. (A) (Kinnula et al., 1995) (Fig. 3). Reduction of the

Heme oxygenases

Heme oxygenase (previously known as heat shock protein 32) (Wong and Wispe, 1997) is a member of the heat-shock family of proteins that plays a protective role in inflammation and oxidative stress (Otterbien and Choi, 2000, Willis et al., 1996). Heme oxygenase catalyzes degradation of heme molecule into bile pigments (biliverdin) in the reaction, which generates carbon monoxide and iron (Tenhunen et al., 1968) (Fig. 4). Heme oxygenase is induced by many stimuli such as hyperoxia, hypoxia,

Thioredoxins

Thioredoxins (MWt, 10–12 kDa) are major ubiquitous disulfide reductases belonging to the flavoprotein family responsible for maintaining proteins in their reduced states. Thioredoxins are dithiol [(SH)2]-disulfide oxidoreductases and catalyze reduction of disulfide to their corresponding sulfhydryls. Thioredoxin system comprises of thioredoxin and thioredoxin reductase components and need reduced nicotinamide adenine dinucleotide phosphate for their function (Fig. 5). Mammalian thioredoxin

Peroxiredoxins

Peroxiredoxins comprise a large group of related proteins, the function of which is to catalyze the degradation of lipid hydroperoxides and hydrogen peroxide (Chae et al., 1994). In excess of 40 gene sequences have been identified to possess homology with the first identified member of the family, yeast thiol sensitive antioxidants, although not all have been assigned a function as yet (Chae et al., 1994). Yeast thiol sensitive antioxidants, now known as Peroxiredoxin I, was first identified as

Glutaredoxins

Glutaredoxins are thiol-disulfide oxidoreductases requiring GSH for their catalytic functions. Glutaredoxins have profound antioxidant capacity and is abundantly present in lungs (Peltoniemi et al., 2004). Glutaredoxins catalyze the reduction of protein disulfide to their respective sulfhydryls by donating reducing equivalents to the oxidized proteins. The oxidized glutaredoxin in turn gets reduced by transfer of reducing equivalents from GSH as shown below:Prot-S-S-Prot + Glutaredoxin SH(red)  

GSH and glutamate cysteine ligase

The GSSG/2GSH ratio can serve as a good indicator of the cellular redox state (Park et al., 1998). This ratio in GSH parlance may be determined by the rates of hydrogen peroxide reduction by glutathione peroxidase and GSSG reduction by glutathione reductase. Thus, antioxidant enzymes play a critical role in the maintenance of the cellular reductive potential. Several enzymes/proteins involved in the redox system of the cell and their genes such as MnSOD, glutamate cysteine ligase catalytic

Conclusions

Antioxidants are major in vivo and in situ defence mechanisms of the cells against oxidative stress. Two classes of antioxidants are recognized: (a) non-enzymatic antioxidants such as Vitamins E, Vitamin C, β-carotene, GSH and (b) enzymatic antioxidants such as GSH redox system comprising of glutamate cysteine ligase, glutathione reductase , glutathione peroxidase, glucose-6-phosphate dehydrogenase, and in addition superoxide dismutases, catalase, heme oxygenase-1, peroxiredoxins, thioredoxins

Acknowledgements

This study was supported by the Environmental Health Sciences Center ES01247.

References (219)

  • R.J. Folz et al.

    Extracellular superoxide dismutase (SOD3): tissue specific expression, genomic characterization, and computer-assisted sequence analysis of the human EC SOD gene

    Genomics

    (1994)
  • R.J. Folz et al.

    Elevated levels of extracellular superoxide dismutase in chronic lung disease and characterization of genetic variants

    Chest

    (1997)
  • R.J. Folz et al.

    Mouse extracellular superoxide dismutase: primary structure, tissue-specific gene expression, chromosomal localization and lung in situ hybridization

    Am. J. Respir. Cell Mol. Biol.

    (1997)
  • M. Gharaee-Kermani et al.

    Lung interleukin-4 gene expression in a murine model of bleomycin-induced pulmonary fibrosis

    Cytokine

    (2001)
  • C.B. Gilks et al.

    Antioxidant gene expression in rat lung after exposure to cigarette smoke

    Am. J. Pathol.

    (1998)
  • B. Halliwell

    Reactive oxygen species in living systems: source, biochemistry, and role in human disease

    Am. J. Med.

    (1991)
  • B. Halliwell et al.

    Free Radicals in Biology and Medicine

    (1989)
  • T. Harju et al.

    Diminished γ-glutamylcysteine synthetase in the airways of smokers'immunoreactivity of lung

    Am. J. Respir. Crit. Care Med.

    (2002)
  • T. Ishii et al.

    Tobacco smoke reduces viability in human lung fibroblasts: protective effect of glutathione S-transferase P1

    Am. J. Physiol., Lung Cell. Mol. Physiol.

    (2001)
  • H.J. Kim et al.

    Preferential elevation of PrxI and Trx expression in lung cancer cells following hypoxia and in human lung cancer tissues

    Cell Biol. Toxicol.

    (2003)
  • I.Y. Adamson et al.

    The pathogenesis of bleomycin-induced pulmonary fibrosis in mice

    Am. J. Pathol.

    (1974)
  • R.G. Allen et al.

    Differences in electron transport potential, antioxidant defences, and oxidant generation in young and senescent fetal lung fibroblasts (WI-38)

    J. Cell. Physiol.

    (1999)
  • J.D. Antuni et al.

    Increase in exhaled carbon monoxide during exacerbations of cystic fibrosis

    Thorax

    (2000)
  • E.S. Arner et al.

    Physiological functions of thioredoxin and thioredoxin reductase

    Eur. J. Biochem.

    (2000)
  • T. Asikainen et al.

    Expression and developmental profile of antioxidant enzymes in human lung and liver

    Am. J. Respir. Cell Mol. Biol.

    (1998)
  • N. Avissar et al.

    Extracellular glutathione peroxidase in human lung epithelial lining fluid and in lung cells

    Am. J. Physiol.

    (1996)
  • N.E. Avissar et al.

    Ozone, but not nitrogen dioxide, exposure decreases glutathione peroxidases in epithelial lining fluid of human lung

    Am. J. Respir. Crit. Care Med.

    (2000)
  • J. Behr et al.

    Pulmonary glutathione levels in acute episodes of farmer's lung

    Am. J. Respir. Crit. Care Med.

    (2000)
  • R.M. Borzi et al.

    Elevated serum superoxide dismutase levels correlate with disease severity and neutrophil degranulation in idiopathic pulmonary fibrosis

    Clin. Sci.

    (1993)
  • B.J. Buckley et al.

    Liposome-mediated augmentation of catalase in alveolar type II cells protects against H2O2 injury

    J. Appl. Physiol.

    (1987)
  • E. Bunnell et al.

    Oxidized glutathione is increased in the alveolar fluid of patients with the adult respiratory distress syndrome

    Am. Rev. Respir. Dis.

    (1993)
  • S.L. Camhi et al.

    Induction of hemeoxygenase-1 gene expression by lipopolysaccharide is mediated by AP-1 activation

    Am. J. Respir. Cell Mol. Biol.

    (1995)
  • A.M. Cantin et al.

    Normal alveolar epithelial lining fluid contains high levels of glutathione

    J. Appl. Physiol.

    (1987)
  • A.M. Cantin et al.

    Oxidant-mediated epithelial injury in idiopathic pulmonary fibrosis

    J. Clin. Invest.

    (1987)
  • M.S. Carraway et al.

    Expression of heme oxygenase-1 in the lung in chronic hypoxia

    Am. J. Physiol., Lung Cell. Mol. Physiol.

    (2000)
  • S. Casagrande et al.

    Glutathiolation of human thioredoxin: a possible crosstalk between the glutathione and thioredoxin systems

    Proc. Natl. Acad. Sci. U. S. A.

    (2002)
    S. Casagrande et al.

    Glutathiolation of human thioredoxin: a possible crosstalk between the glutathione and thioredoxin systems

    Cell. Mol. Biol.

    (2000)
  • F. Chabot et al.

    Reactive oxygen species in acute lung injury

    Eur. Respir. J.

    (1998)
  • H.Z. Chae et al.

    Cloning and sequencing of thiol-specific antioxidant from mammalian brain: alkyl hydroperoxide reductase and thiol-specific antioxidant define a large family of antioxidant enzymes

    Proc. Natl. Acad. Sci. U. S. A.

    (1994)
  • L.Y. Chang et al.

    Immunocytochemical localization of the sites of superoxide dismutase induction by hyperoxia in rat lungs

    Lab. Invest.

    (1995)
  • A.M.K. Choi et al.

    Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury

    Am. J. Respir. Cell Mol. Biol.

    (1996)
  • F.F. Chu et al.

    Expression, characterization and tissue distribution of new cellular glutathione peroxidase, GSHPx-GI

    J. Biol. Chem.

    (1993)
  • L.B. Clerch et al.

    Early divergent lung antioxidant enzyme expression in response to lipopolysaccharide

    Am. J. Physiol.

    (1996)
  • B.L. Clyde et al.

    Distribution of manganese superoxide dismutase mRNA in normal and hyperoxic rat lung

    Am. J. Respir. Cell Mol. Biol.

    (1993)
  • R.K. Coker et al.

    Pulmonary fibrosis: cytokines in the balance

    Eur. Respir. J.

    (1998)
  • S.A.A. Comhair

    The regulation and role of extracellular glutathione peroxidase

    Antioxid. Redox Signal.

    (2005)
  • S.A. Comhair et al.

    Antioxidant responses to oxidant-mediated lung diseases

    Am. J. Physiol., Lung Cell. Mol. Physiol.

    (2002)
  • S.A. Comhair et al.

    Differential induction of extracellular glutathione peroxidase and nitric oxide synthase 2 in airways of healthy individuals exposed to 100% O(2) or cigarette smoke

    Am. J. Respir. Cell Mol. Biol.

    (2000)
  • S.A. Comhair et al.

    Extracellular glutathione peroxidase induction in asthmatic lungs: evidence for redox regulation of expression in human airway epithelial cells

    FASEB J.

    (2001)
  • S.A. Comhair et al.

    Correlation of systemic superoxide dismutase deficiency to airflow obstruction in asthma

    Am. J. Respir. Crit. Care Med.

    (2005)
  • S.A. Comhair et al.

    Superoxide dismutase inactivation in pathophysiology of asthmatic airway remodeling and reactivity

    Am. J. Pathol.

    (2005)
  • Cited by (599)

    View all citing articles on Scopus
    View full text