ReviewOxidant and antioxidant balance in the airways and airway diseases
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.
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