July - September 2007: 
Volume 20, Issue 3

Click on the image to download the Issue in PDF format.


Οxidative stress and its control in the lung
SUMMARY. Due to its large surface area and its rich blood supply, the lung is susceptible to oxidative injury by many reactive oxygen species and free radicals. The main sources of oxidants affecting the lung include external agents (smoke, radiation, carcinogens, drugs, ozone, hyperoxia) and cellular mechanisms (inflammatory cells such as neutrophils, eosinophils, macrophages, fibroblasts, endothelial cells, xanthine and NADPH oxidases). Via these sources oxygen and nitrogen reactive species are produced, which exert the final harmful effect of cell damage. The major oxidative agents are the superoxide anion, hydrogen peroxide, the hydroxyl radical, nitric oxide, etc. Antioxidants help the lung to ward off the consequences of the oxidative injury. Antioxidant defenses include non-enzymatic agents (vitamins C and E, beta-carotene, uric acid) and enzymes (dismutase, catalases and peroxidases). New research has revealed the activity in antioxidant defense at a more subtle level of low molecular weight proteins such as oxygenase-heme, thioredoxins, etc. The susceptibility of the lung to oxidant injury depends mainly on the degree of its ability to upregulate the antioxidant defenses, which means that the various lung diseases attributed to oxidative injury could possibly be controlled by the antioxidant mechanisms at the cellular level or even at the level of gene expression. Antioxidant defense may be present at both cell and mRNA expression level, but antioxidant activity is the critical factor in the development and progression of lung disease. Pneumon 2007; 20(3):289-292
Full text


The lung is the organ with the highest exposure to atmospheric oxygen. Due to its large surface area and rich blood supply, the lung is susceptible to oxidative injury by large numbers of reactive oxygen species (ROS) and nitrogen species, as well as by free radicals. In situ lung injury due to ROS is strongly associated with oxidation of proteins, lipids and DNA. These oxidized biomolecules may also induce a variety of cellular responses with generation of secondary metabolic species1.

At the biochemical level, ROS inactivate antiproteases, induce apoptosis, regulate cell proliferation and modulate the immune response of the lungs.At the molecular level, ROS and nitrogen species have been implicated in initiating inflammatory responses through the activation of transcription factors such as NF-kb and protein AP-1. In addition they modulate the gene expression of pro-inflammatory mediators2.

In a parallel course with oxidative mechanisms there is a reaction by agents called antioxidants designed to suppress the harmful effects of ROS. The major nonenzymatic antioxidants in the lung include glutathione (GSH), vitamins E and C, beta carotene and uric acid. The enzymatic antioxidants include superoxide dismutases (SODs), catalase and peroxidases. These antioxidant agents constitute the first line of defense against oxidants, acting at the supracellular level, while at the cellular level there is a second line of antioxidant defense involving certain specialized proteins, such as peroxiredoxins, heme oxygenases and reductases.

The source of ROS in the lungs

The sources of ROS can be divided into external and cellular (figure 1). External sources include smoking, radiation, carcinogens, drugs, hypoxia and ozone exposure3. Cellular sources include inflammatory cells, fibroblasts, endothelial cells and oxidases (xanthine -NADPH) 4.

The most important ROS are the superoxide anion (O2-), the hydroxyl radical (OH), nitric oxide (NO) and hydrogen peroxide (Η2Ο2). Mechanisms of ROS production are summarized in figure 1. The primary and most important ROS are O2 - and Η2Ο2 , but the most reactive and harmful is the OH radical, which is formed either from Η2Ο2 and O2- or via the reaction of O2- and NO, with the production of peroxynitrate which then decomposes to form nitrogen dioxide and OH5.

The gaseous form of cigarette smoke contains more than 1015 ROS per puff, and high concentrations of O2- and NO. The tar from cigarettes contains organic free radicals, which react with molecular oxygen producing O2-, OH and Η2Ο2. The cycle of oxidative stress is sustained by antioxidant mechanisms such as GSH, NADPH and ascorbic acid, which initially reduce the oxidative load to its original reduced state, but simultaneously enable it to start reproduction of the superoxide radical. The main cellular sources of ROS include neutrophils, eosinophils and alveolar macrophages, but also epithelial cells, fibroblasts and endothelial cells6.

Oxidative stress in lung diseases

The increased oxidative stress observed in many lung diseases may arise from the specific accumulation of various inflammatory cells, different for each disease. Many cytokines are involved in the process, either as chemoattractants of inflammatory cells or through direct or indirect regulation by ROS. Oxidative stress is increased in bronchial asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis and acute respiratory distress syndrome (ARDS)7. External sources of ROS, such as hyperoxia are considered responsible for diseases such as bronchopulmonary dysplasia in preterm infants8. In smoking related lung diseases an excessive load of oxidative stress is produced, from the smoke itself and/or from the specific inflammatory process predominating in each disease. Evaluation of ROS is based on both invasive, i.e., bronchoscopy with bronchoalveolar lavage (BAL) and non-invasive, i.e. exhaled air biomarkers (EBC), procedures 9.

Antioxidant mechanisms

Antioxidant mechanisms can be divided into enzymes, the main representatives being dismutases, catalases, glutathione peroxidase, hemes and low molecular weight redox proteins, and non-enzymatic antioxidants, which are mainly low molecular weight species.

The most important issue for antioxidant agents is their concentrations in the systemic circulation and in the epithelial lung fluid (ELF). For example, uric acid is found in high concentrations in plasma and low in ELF, while the converse is observed for glutathione1.

Table 1 summarizes the main antioxidant agents, their cellular distribution, their functional activity and their linkage with respiratory diseases.

Dismutases are overexpressed in the epithelium of interstitial lung diseases, while they show reduced expression in the epithelium of smokers. One plausible explanation for these observations might lie in the different activity of gene expression at cellular and molecular levels. Catalases show remarkable reactivity in alveolar macrophages, while their gene expression in smokers is not upregulated. Enzymes related to glutathione metabolism show diversity in both immunoreactivity and gene expression. This diversity could be attributed clinically to the balance between smoking and the presence of airway obstruction10. Specifically GPX3 enzyme is increased in the epithelium of smokers but is extremely low in patients with emphysema11. Similar biological behaviour is also observed with other enzymes such as GST and GPX, which are upregulated in alveolar macrophages. Heme-oxygenase showed increased immunoreactivity in the alveoli of normal subjects, but decreased expression in patients with COPD12.

To summarize, antioxidants constitute major in vivo and in situ defense mechanisms against oxidative stress. Two classes of antioxidants are recognized, which often work synergistically and are both involved in the redox cycling process. Depending on their expression at the cellular level, and according to their gene load, they participate actively in the development and progression of various lung diseases.

The balance of oxidant and antioxidant activity in the lung appears to be modulated and regulated by both molecular and genetic mechanisms, which according to their expression can lead to or suppress the development of airway disorders.


1. Rahman I, Biswas S, Kode A. Oxidant and antioxidant balance in the airways and airways diseases. Eur J of Pharmacology 2006; 533:222-39.
2. Rahman I, MacNee W. Role of transcription factors in inflammatory lung diseases. Thorax 1998; 53:601-12.
3. Nagai K, Betsuyaku T, Kondo T, et al. Long term smoking with age builds up excessive oxidative stress in bronchoalveolar lavage fluid. Thorax 2006; 61:496-502.
4. Ichinose M, Sugiura H, Yamagata S, et al. Xanthine oxidase inhibition reduces reactive nitrogen species production in COPD airways. Eur Respir J 2000; 22:457-61.
5. Comhair SA, Erzurum SC. Antioxidant response to oxidant mediated lung diseases. Am J Physiol Lung Cell Mol Physiol 2002; 283:L246-L255.
6. Aoshiba K, Yasuda K, Yasui S, et al. Serine proteases increase oxidative stress in lung cells. Am J Physiol Lung Cell Mol Physiol 2001; 281:L556-L564.
7. Kinnula VL. Focus on antioxidant enzymes and antioxidant strategies in smoking related airway diseases. Thorax 2005; 60:693–700.
8. Wang Y, Phelan SA, Manevich Y, et al. Transgenic mice overexpressing peroxiredoxin 6 show increased resistance to lung injury in hyperoxia. American Journal of Respiratory Cell and Molecular Biology 2006; 34:481-86.
9. Kharitonov SA, Barnes PJ. Exhaled biomarkers. Chest 2006; 130:1541-6.
10. Juul K, Tybjaerg-Hansen A, Marklund S, et al. Genetically Increased Antioxidative Protection and Decreased Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2006; 173:858-64.
11. MacNee W. Oxidants/antioxidants and COPD. Chest 2000; 117:303S-17S.
12. Maestrelli P, Paska C, Saetta M, et al. Decreased haem oxygenase- 1 and increased inducible nitric oxide synthase in the lung of severe COPD patients. Eur Respir J 2003; 21:971-6.