Title: Oxidative stress and the lung


Key words: oxidative stress, inflammatory disorders, ageing, cancer, oxygen, superoxide, xanthine oxidase, oxidases, antioxidant, defences, cystic fibrosis, asthma, adult respiratory distress syndrome, ARDS, respiratory, tract, bronchoalveolar, lavage, vitamin C, vitamin E, albumin, caeruloplasmin, transferrin, superoxide dismutase, catalase, glutathione peroxidase, pulmonary fibrosis, ozone, oxidative stress, free radicals, urate, exposure chambers, airways, hypersensitivity, plasma, atopic, atopy, hydroxyl radical, hydrogen peroxide, myeloperoxidase, hypochlorite, elastase, ascorbate, peroxynitrite, transudates, nitrosation, secondary infection, cytotoxic, cytotoxicity, pseudomonas aeruginosa, neutrophils, leucocytes, mitochondrial DNA, ageing, supplementation, antioxidants,  


Date: Sept 2006




Nutrimed Module:


Type: Article


Author: Morgan, G


Oxidative stress and the lung 




Oxidative stress has been implicated in a wide range of degenerative disorders from inflammatory disorders and cardiovascular disease to ageing and cancer (Halliwell 1999). Oxygen itself is a toxic agent, acting by increasing superoxide production through activation of xanthine oxidase and other oxidases (Turrens 1982). The antioxidant defences of the lung are of prime importance in protecting the body from oxidising agents such as the superoxide radical. Where the antioxidant defences of the lung are known to be impaired, free radical damage to lipids and proteins can occur. Cystic fibrosis, adult respiratory distress syndrome (ARDS) and asthma are such examples (Van der Vliet 1996, Haddad 1994, Quinlan 1996, Owen 1991). This review will look at the extent of this defence system and the nature of the oxidative stress that causes it to break down in a variety of diseases.


Respiratory tract lining fluid (RTLF)

RTLF is the first line of defence for the lung.

Bronchoalveolar lavage has shown that the RTLF contains a range of antioxidants and antioxidant enzyme systems, including vitamins C and E, urate, albumin, caeruloplasmin, transferrin, superoxide dismutase , catalase and glutathione peroxidase (Davis 1991). Glutathione and vitamin C are present in particularly high amounts in normal lung (Cantin 1987). Levels are known to be increased in asthma and depressed in ARDS and idiopathic pulmonary fibrosis (Smith L J 1993). Experiments in animals have shown elevations of glutathione levels in RTLF following oxidative stress with ozone (Boehme 1992). In humans, exposure in experimental chambers has shown progressive exhaustion of vitamin C levels with increasing ozone concentrations (Kelly 2002). Similar changes have been demonstrated with vitamin C and urate in RTLF on exposure to nitrogen dioxide, another free radical gas (Kelly 1996). Lung injury from whatever cause is known to cause transudation of fluids rich in the antioxidants albumin and urate which offer protection against further oxidative damage (Liu 1991). That these local antioxidant levels reflect total body stores is suggested by reduced plasma antioxidant levels in asthma, cystic fibrosis and ARDS (Hatch 1995, Flat 1990, Brown and Kelly 1994, Louie 1983).


Humoral and inflammatory pathways associated with oxidative stress

Exposure chamber experiments have shown acute ozone exposure to cause inflammatory changes of the airways at concentrations below those found in the UK (Am Thor Soc 1996). This corresponds with the extremely irritant nature of this oxidant which is known to increase the hospital admission rate in healthy subjects during the summer months (Stedman 1997). Hypersensitivity of the airways is thought to be modulated by complement, cytokines and pro-inflammatory prostaglandins leading to respiratory compromise (Pryor 1993). Other free radicals, notably nitric oxide and nitrogen dioxide, present in exhaust fumes and industrial pollution in urban areas, have a similar effect. Antioxidants in the plasma and RTLF have been shown to reduce this response in animals (Matsui 1991), and beneficial effect in humans has been demonstrated (Hatch 1995).


In atopic states such as asthma, oxidative stress may be compounded through humoral and inflammatory pathways. Bronchoalveolar lavage in asthma shows invasion of the RTLF with mast cells, eosinophils and neutrophils and the presence of high concentrations of histamine, complement, cytokines and prostaglandins (Smith DL 1993). Activated eosinophils and neutrophils serve as major producers of free radicals such as superoxide, hydroxyl radical and hydrogen peroxide (Smith LJ 1993). Such radicals lead to lipid and protein oxidation, inflammatory changes and disruption of normal haemoglobin biochemistry, all of which may lead to disturbances of oxygen transport (Babior 1987).


Myeloperoxidase release associated with phagocytosis also leads to the formation of the hypochlorite radical. This can lead to inactivation of the acute phase protein alpha 1- antiproteinase which helps to suppress elastase activity. Elastase promotes hydrolysis of the matrix protein elastin leading to disruption of the normal lung cytoarchitecture and the evolution of emphysematous changes (Weiss 1989).

In asthma, ascorbate and other antioxidants help to scavenge free radicals such as superoxide, hypochlorite and peroxynitrite, and assist in protecting alpha 1-proteinase activity. Inflammatory changes leading to transudates rich in such antioxidants as vitamin C, urate, albumin and caeruloplasmin are thought to increase this effect, limiting further oxidative damage (Liu 1991). In cases of ARDS and nitrogen dioxide toxicity, it is known that these defences can be overwhelmed leading to alpha 1-proteinase suppression, lipid and protein peroxidation and nitrosation, and signs of oxidative lung damage (Cochrane 1983,Halliwell 1999). Reduced plasma levels of vitamin C and RTLF levels of glutathione appear to reflect this level of oxidative stress (Louie 1996). Asthmatics also show reduced levels of vitamin C, though the results of supplementation have been found to be inconsistent in trials (Hatch 1995). Elevation of RTLF glutathione in asthmatics may represent adaptation to chronic oxidative stress (Smith LJ 1993).


Infection as a promoter of oxidative stress

Secondary infection presents a further oxidative challenge to a stressed respiratory tract and is of particular importance in the case of cystic fibrosis and asthma. Secondary infection in cystic fibrosis with the organism Pseudomonas aeruginosa is prevalent and is of major concern. Not only is it multiply resistant to antibiotics but it is particularly virulent through its ability to generate hydroxyl and other free radicals. These, in combination with reactive oxygen species generated by accompanying neutrophils and macrophages, have been shown to be cytotoxic to respiratory endothelial cells (Britigan 1992). A thousand-fold increase in the numbers of neutrophils present in the RTLF of cystic fibrosis represents a major oxidative stress factor (Brown 1994, Holsclaw 1993) and undoubtedly is reflected in the reduced RTLF glutathione levels in these cases (Roum 1990).


High leucocyte counts present in asthmatic RTLF are largely modulated by immunological pathways. Release of free radicals through these pathways is sufficiently high to allow detection of hydrogen peroxide and nitric oxide in the breath of asthmatics (Silvestri 2001). Such an environment is not conducive to bacterial invasion of the respiratory tract but, should it occur, the oxidative stress burden would be increased yet further.


Metabolic factors associated with oxidative stress

An increase in mitochondrial activity has been demonstrated in cystic fibrosis (Feigal 1979). Such an acceleration of the electron transport chain is associated with increased production of reactive oxygen species. Damage to mitochondrial DNA through increased free radical activity also leads to leakage of superoxide and may be a factor in this and other lung conditions such as asthma where chronic inflammation or infection play a part (Von Ruecker 1984). Ageing itself accelerates these changes and may be important in cystic fibrosis (Shigenaga 1994).



Adaptation has been shown to occur as a response to oxidative stress (Jac. Thus, in animal experiments, repeated exposure to ozone leads to decreased airway irritability, indicating an improved antioxidant status (Jackson 1984). Increased superoxide dismutase and vitamin C levels have been associated with this adaptation (Crapo 1974). This highlights the fact that the antioxidant protection provided by the RTLF is limited when subjected to acute exposure to noxious free radicals such as ozone or nitrogen dioxide. Exposure chamber experiments in humans are in keeping with these conclusions (Kelly 2002).


In ARDS acute infiltration of the respiratory tract by leucocytes generating free radicals appears to overwhelm the limited capacity of the RTLF to sustain the oxidative challenge presented. In the more chronic conditions of cystic fibrosis and asthma, adaptation of the RTLF would appear to be better able to protect the respiratory tract against the combined metabolic, immunologic and infective challenge to the lung’s antioxidant system. Limitations to the system are highlighted by the increased vulnerability of cystic fibrosis patients to infection and the increased sensitivity of asthmatics to atmospheric pollution with ozone and nitrogen dioxide (Cross 1997, Romieu 1997).


The corollary to these adaptations is that supplementation with antioxidants is limiting to free radical lung damage. Supplementation is now an integral part of the chronic management of cystic fibrosis and RTLF antioxidant levels have been found to be better maintained in such patients (Brown 1994). Allowing for improvements in general care, given what we know of the destructive effects of unbridled oxidant activity, it is likely that much of the improvement in life expectancy is due to this factor. Antioxidants have also been shown to be of benefit in acute disorders such as ARDS (Suter 1994). Further research into the interplay between oxidative stress and the antioxidant system is called for in these and other lung conditions.



1. Halliwell B, Gutteridge JMC (1999) Free radicals in biology and medicine. 3rd ed. Oxford University Press

2. Turrens JF, Freeman BA, Levitt JG, Crapo JD (1982) The effect of hyperoxia on superoxide production by lung submitochondrial particles. Arch Biochem Biophys 217: 401-410

3. Van der Vliet A, et al. (1996) Oxidative stress in cystic fibrosis: does it occur and does it matter? Adv Pharmacol 38: 491

4. Haddad IM, et al. (1994) Quantification of nitrotyrosine levels in lung sections of patients and animals with acute lung injury. J Clin Invest 94: 2407-2413

5. Quinlan GL, Lamb NJ, Evans TW, Gutteridge JMC (1996) Plasma fatty acid changes and increased lipid peroxidation in patients with adult respiratory distress syndrome. Crit Care Med 24: 241-46

6. Owen S, Pearson D, Suarez-Mendez V, O’Driscoll R, Woodcock A (1991) Evidence of free radical activity in asthma. N Eng J Med

325: 581-7

7. Davis WB, Pacht ER (1991) Extracellular antioxidant defences. In: Crystal RG, West WB, eds. The lung: scientific foundations. New York, Raven Press

8. Cantin AM, North SL, Hubbard RC, Crystal RG (1987) Normal alveolar epithelial lining fluid contains high levels of glutathione. J Appl Physiol 63: 157-63

9. Smith LJ, Houston M, Anderson J (1993) Increased levels of glutathione in bronchoalveolar lavage fluids from patients with asthma. Ann Rev Resp Dis 147: 1461-146

10. Boehme DS, Hotchkiss JA, Henderson RF (1992) Glutathione and GSH-dependent enzymes in bronchoalveolar lavage fluids in response to ozone. Exp Mol Pathol 56: 37-48

11. Kelly FJ (2002) Lecture notes. Surrey University

12. Kelly FJ, et al. (1996) Antioxidant kinetics in lung lavage fluid following exposure of humans to NO2. Am J Resp Crit Care Med 154: 1700

13. Liu MC, et al. (1991) Immediate and late inflammatory responses to ragweed antigen challenge of the peripheral airways in allergic asthmatics. Ann Rev Resp Dis 144: 51-8

14. Hatch GE (1995) Asthma, inhaled oxidants, and dietary antioxidants.  Am J Clin Nutr 61: 625S

15. Flat A, et al. (1990) Reduced selenium in asthmatic subjects in New Zealand. Thorax 45: 95-9

16. Brown RK and Kelly FJ (1994) Role of free radicals in the pathogenesis of cystic fibrosis. Thorax 49: 738-742

17. Louie S, et al. (1996) ARDS: a radical perspective. Adv Pharmacol 38: 457

18. American Thoracic Society (1996) Health effects of outdoor air pollution. Am J Resp Crit Care Med 153: 3-50

19. Stedman JR, Anderson HR, Atkinson RW, Maynard RL (1997) Emergency hospital admissions for respiratory disorders attributable To summer time ozone episodes in Great Britain. Thorax 52:958-63 20. Pryor WA (1993) Ozone in all its reactive splendor. J Lab Clin Med    122: 483-6 21. Matsui S (1991) The effect of antioxidants on ozone-induced airway hyperresponsiveness in dogs.

22. Smith DL, Deshago RD (1993) Bronchoalveolus lavage in asthma. Ann Rev Resp Dis 148: 523-532

23. Babior BM (1987) Superoxide: a two-edged sword. Brazil J Med Biol Res 30: 141

24. Weiss SJ (1989) Tissue destruction by neutrophils. N Eng J Med  320: 365

25. Cochrane CG, Spragg R, Revak SD (1983) Pathogenesis of the adult respiratory distress syndrome: evidence of oxidant activity in bronchoalveolar lavage fluid. J Clin Invest 71: 754-761

26. Britigan BE, et al (1992) Interaction of Pseudomonas aeruginosa secretory products pyocyanin and pyochelin generates hydroxyl radical and causes synergistic damage to endothelial cells. Implications for Pseudomonas-associated tissue injury. J Clin Invest 90: 2187-96

27. Brown RK, Kelly FJ (1994) Evidence for increased oxidative damage in patients with cystic fibrosis. Pediatr Res 36: 487-491

28. Holsclaw DS (1993) Cystic fibrosis and pulmonary involvement from      multiple perspectives. Semin Resp Infect 7: 141-150

29. Roum JH, et al. (1990) Cystic fibrosis is characterised by a marked reduction in glutathione levels in pulmonary epithelial lining fluid.

30. Silvestri M, et al. (2001) Exhaled nitric oxide levels in non-allergic and allergic mono- or polysensitised children with asthma. Thorax 56: 857-62

31. Feigal RJ, Shapiro BL (1979) Mitochondrial calcium uptake and oxygen consumption in cystic fibrosis. Nature 278: 276-7

32. Von Ruecken AA, Bertele R, Harms HK (1984) Calcium metabolism and cystic fibrosis: mitochondrial abnormalities suggest a modification of the mitochondrial membrane.

33. Shigenaga MK, et al. (1994) Oxidative damage and mitochondrial decay in ageing. Proc Natl Acad Sci USA 91: 10771 34. Jackson JH (1994) Potential molecular mechanisms of oxidant-induced carcinogenesis. Env Health Perspect 102: 155

35. Crapo JD, Tierney DF (1974) Superoxide dismutase and pulmonary oxygen toxicity. Am J Physiol 226: 1401-07

36. Cross CE, et al. (1997) General biological consequences of inhaled environmental toxicants. In: The lung: scientific foundations. Crystal RG, et al. eds., p2421. Raven Press, Philadelphia

37. Romieu I (1997) Effects of intermittent ozone exposure on peak expiratory flow and symptoms among asthmatic children in Mexico  City. Arch Environ Health 52: 368-76

38. Suter PM, et al. (1994) N-acetylcysteine enhances recovery from acute lung injury in man. Chest 105: 190-194