The two faces of antioxidants in pulmonary vascular disease: Focus on COPD

PVRI Member Authors: Michael Seimetz, Djuro Kosanovic, Himal Luitel, Ralph T. Schermuly, Michiel Alexander de Raaf, Harm-Jan Bogaard, Eveline Baumgart-Vogt, Norbert Weissmann, Srikanth Karnati

Prelude

Based on a variety of scientific reports, but also on sales promotion, antioxidants became quite popular dietary supplements. People thought and still believe antioxidants would reduce disease, boost system performance and perhaps even slow the aging clock. But the reality is not quite so glorious. It is true that in some cases, high amounts of antioxidants are helpful. However, in other cases they can be harmful. It is only a slight exaggeration to say that for every study that shows benefits, there is another study that does not. In terms of diseases associated with oxidative stress, such as chronic obstructive pulmonary disease (COPD), antioxidant supplementation may make sense. Yet even so, some studies showed beneficial effects on the health of COPD patients, and other studies demonstrated that there was no difference between antioxidant-treated and placebo-treated patients. Thus, there is a controversy which will be discussed in this article. This interactive discussion aims to challenge scientists and other persons who are interested in this field to express their views about the usefulness of antioxidant supplementation for the treatment of pulmonary diseases associated with, but also independent of oxidative stress.

 Oxidants and oxidative/carbonyl stress

Based on the anatomy (high blood supply and large surface area) and physiological role of the lungs, they are permanently exposed to high oxygen levels. Furthermore, the lung epithelium is constantly exposed to endogenous oxidants produced during mitochondrial respiration and by activated inflammatory cells. But also exogenous sources of oxidants such as cigarette smoke and air pollutants, e.g. ozone, combustion particles and nitrogen dioxide, affect the lung epithelium.1 Under normal conditions there is a balance of oxidants and antioxidants to ensure critical amounts of oxidants do not occur. Under pathological conditions, such as COPD, there is an oxidant/ antioxidant imbalance in favor to oxidants resulting in oxidative and subsequent carbonyl stress.2,3 Oxidative stress is mediated by reactive oxygen species (ROS), either nonradical (hydrogen peroxide) or oxygen radicals (superoxide, hydroxyl radical). The unstable radicals with unpaired electrons can initiate oxidations themselves, or together with reactive nitrogen species, they can cause a couple of harmful effects such as apoptosis, cell necrosis, senescence, autophagy, inflammation, epigenetic changes, remodeling of extracellular matrix and blood vessels, endothelial dysfunction, inactivation of antiproteases, mucus hypersecretion, worsened tissue repair, lipid peroxidation and protein carbonylation (Figure 1).4 Carbonyl stress, a consequence of oxidase stress and the accumulation of carbonylated proteins whose functions are altered, is increasingly recognized as a major driver for chronic diseases5 and is present in both smokers and COPD patients.6,7

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Figure 1: Oxidative stress-related pathogenesis of COPD. Oxidative stress derived from several sources, such as cigarette smoke, inhaled oxidants and endogenous reactive oxygen species (ROS) can lead to inflammation and an imbalance of oxidants and antioxidants in favor to oxidants. This in turn results in various cellular and molecular alterations leading to COPD/emphysema. The usage of antioxidant supplementation in oxidative stress-related disorders is reasonable, but still questionable and under debate respectively. Modified from Rahman and MacNee, Current Opinion in Pharmacology 2012, 102:256-265

Excessive amounts of oxidants can lead to oxidation of essential molecules in the organism. For instance, molecules of the vasculature that form the walls of arteries, become oxidized when they lose an electron. Once oxidized, they become unstable and easily break apart. Moreover, oxidative stress can result in enhanced inflammatory gene expression, failure to resolve the inflammatory response, corticosteroid insensitivity, a decreased capacity to induce endogenous antioxidant defenses, and a rapidly aging lung in COPD with increased risk of developing emphysema.3 However, not all free radicals are bad. In fact, free radicals are necessary for life. For instance, the organism cannot turn air and food into chemical energy without a chain reaction of free radicals. Free radicals are a natural byproduct of breathing. They are also a crucial part of the immune system by attacking foreign invaders, such as bacteria. They can also act as second messengers and thereby play an important role in signal transduction.3,8 Antioxidants as dietary supplements Antioxidants have the ability to neutralize oxidants and protect the body against oxidative stress. Some of the most common antioxidants are the vitamins C and E, selenium and beta carotene. Over the last two decades, a number of studies have suggested that COPD risk is associated with diets lacking in vitamins and antioxidants. Low diet-intake of vitamins has been reported to reduce natural defenses and increase the probability of airway inflammation.9 Furthermore, a high intake of fruits and vegetables has been associated with a lower risk of COPD, lower mortality and an improvement of spirometric values.9-16 A profound systematic review by Tsiligianni and van der Molen17 revealed that a variety of studies and reviews highlight an association of vitamins with lung function in healthy subjects and COPD patients and a reduction in symptoms, respiratory infections and exacerbations. Moreover, it is suggested that an increased vitamin intake may reduce the annual decline of FEV1 (forced expiratory volume in 1 second). However, there was no clear evidence of the benefit of vitamin supplements. Most studies regarding supplements showed no benefit of multivitamin supplementation in symptoms, spirometric function or hospitalization for COPD.17

The epithelial lining fluid, which protects the surface of the lung from the environment, contains several antioxidants including ascorbic acid (vitamin C), α-tocopherol (vitamin E), and uric acid. Several studies have shown a clear association between reduced levels of vitamin C and E and worsened pulmonary function in COPD. However, this may simply reflect an increased oxidative burden as a result of repeated exacerbations.3 To date, there are no studies clearly showing that dietary supplementation with antioxidants can lead to clinical improvement.17 However, a 10-year follow-up study did find that antioxidant supplementation reduced the risk of of the development of chronic lung disease by 10%18 and lowered carbonyl stress levels in the lung.19 Although there initially was enthusiasm for the use antioxidants for prevention of disease and improvement of health, over the years neutral and even negative reports surfaced about the benefits of antioxidant supplements. As an example, in 1994, a study published in the New England Journal of Medicine reported that there was no reduction in the incidence of lung cancer among Finnish male smokers after five to eight years of dietary supplementation with vitamin E or beta carotene. In contrast, the smokers receiving a beta carotene supplement were 18 percent more likely to develop lung cancer.20

 The explanations why antioxidant supplementation does not work satisfactorily in most of the patients suffering from oxidative stress-related diseases are manifold and remain in part speculative. One important issue seems to be the role of ROS in signal transduction3,8 and immune response which may be abolished by high doses of antioxidants. Moreover, the term ‘antioxidant paradox’ should be mentioned. It is “often used to refer to the observation that oxygen radicals and other ROS are implicated in several human diseases, but giving large doses of dietary antioxidants to human subjects has, in most studies, had little or no preventative or therapeutic effect”.21,22 The author Barry Halliwell, a pioneer in the field of free radicals and antioxidants, has some interesting explanations regarding his introduction of the term ‘antioxidant paradox’. He suggests that high amounts of antioxidants might be turning into pro-oxidants, fueling free-radical production and its damage. This theory is supported by findings from Carr and Frei.23 However, low levels of pro-oxidants can be good, exerting a mild stressful challenge that triggers a rapid response, leading to increased levels of endogenous antioxidant defense systems.22 This dose-dependency of pro-oxidants is consistent with Paracelsus´ popular sentence: Dosis facit venenum - The dose makes the poison. Furthermore, the time point of application can also be critical. Vitamin C can worsen cell damage once it has already started. Several studies have shown that people who did not get the daily recommended allowance of vitamin C had an increase in free-radical damage to their DNA. But, paradoxically, people who took megadoses of vitamin C also had an increase in DNA damage.

Halliwell argues that a varied diet seems to be healthier than simple supplement-taking because the isolated antioxidant might not be sufficient. Fruits and vegetables are rich in antioxidants and contain hundreds of other chemicals. It is unlikely that any single chemical or combination of chemicals might pack the therapeutic punch.

Finally, according to Halliwell, to minimize oxidative damage, one should eat well including plenty of fruits, grains and vegetables, avoid obesity, not smoke and exercise regularly (also a mild pro-oxidant challenge that triggers beneficial adaptation).22

The question for interactive discussion

Based on the existing controversies regarding the beneficial effects of antioxidant supplementation, we would like to postulate the question: Should antioxidant supplements be used in oxidative stress-related pulmonary diseases or is it just a waste of money, effort or even harmful? We invite all experts and persons/scientists interested in this field to reply and express their valuable views on this important scientific and clinical issue, in the next volume of PVRI Chronicle.

References

 1. Rahman, I., and MacNee, W. 2012. Antioxidant pharmacological therapies for COPD. Curr Opin Pharmacol 12:256-265.

2. MacNee, W., and Rahman, I. 2001. Is oxidative stress central to the pathogenesis of chronic obstructive pulmonary disease? Trends Mol Med 7:55-62.

3. Kirkham, P.A., and Barnes, P.J. 2013. Oxidative stress in COPD. Chest 144:266-273.

4. Yao, H., and Rahman, I. 2011. Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease. Toxicol Appl Pharmacol 254:72-85.

 5. Negre-Salvayre, A., Coatrieux, C., Ingueneau, C., and Salvayre, R. 2008. Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors. Br J Pharmacol 153:6-20.

6. Kirkham, P.A., Caramori, G., Casolari, P., Papi, A.A., Edwards, M., Shamji, B., Triantaphyllopoulos, K., Hussain, F., Pinart, M., Khan, Y., et al. 2011. Oxidative stressinduced antibodies to carbonyl-modified protein correlate with severity of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 184:796-802.

7. Kluchova, Z., Petrasova, D., Joppa, P., Dorkova, Z., and Tkacova, R. 2007. The association between oxidative stress and obstructive lung impairment in patients with COPD. Physiol Res 56:51-56.

8. Park, H.S., Kim, S.R., and Lee, Y.C. 2009. Impact of oxidative stress on lung diseases. Respirology 14:27-38.

9. Heffner, J.E., and Repine, J.E. 1989. Pulmonary strategies of antioxidant defense. Am Rev Respir Dis 140:531- 554.

10. Brug, J., Schols, A., and Mesters, I. 2004. Dietary change, nutrition education and chronic obstructive pulmonary disease. Patient Educ Couns 52:249-257.

11. Carey, I.M., Strachan, D.P., and Cook, D.G. 1998. Effects of changes in fresh fruit consumption on ventilatory function in healthy British adults. Am J Respir Crit Care Med 158:728-733.

12. Denny, S.I., Thompson, R.L., and Margetts, B.M. 2003. Dietary factors in the pathogenesis of asthma and chronic obstructive pulmonary disease. Curr Allergy Asthma Rep 3:130-136.

13. Strachan, D.P., Cox, B.D., Erzinclioglu, S.W., Walters, D.E., and Whichelow, M.J. 1991. Ventilatory function and winter fresh fruit consumption in a random sample of British adults. Thorax 46:624-629.

14. Tabak, C., Arts, I.C., Smit, H.A., Heederik, D., and Kromhout, D. 2001. Chronic obstructive pulmonary disease and intake of catechins, flavonols, and flavones: the MORGEN Study. Am J Respir Crit Care Med 164:61-64.

15. Tabak, C., Feskens, E.J., Heederik, D., Kromhout, D., Menotti, A., and Blackburn, H.W. 1998. Fruit and fish consumption: a possible explanation for population differences in COPD mortality (The Seven Countries Study). Eur J Clin Nutr 52:819-825.

16. Walda, I.C., Tabak, C., Smit, H.A., Rasanen, L., Fidanza, F., Menotti, A., Nissinen, A., Feskens, E.J., and Kromhout, D. 2002. Diet and 20-year chronic obstructive pulmonary disease mortality in middle-aged men from three European countries. Eur J Clin Nutr 56:638-643.

17. Tsiligianni, I.G., and van der Molen, T. 2010. A systematic review of the role of vitamin insufficiencies and supplementation in COPD. Respir Res 11:171.

18. Agler, A.H., Kurth, T., Gaziano, J.M., Buring, J.E., and Cassano, P.A. 2011. Randomised vitamin E supplementation and risk of chronic lung disease in the Women’s Health Study. Thorax 66:320-325.

19. de Batlle, J., Barreiro, E., Romieu, I., Mendez, M., Gomez, F.P., Balcells, E., Ferrer, J., Orozco-Levi, M., Gea, J., Anto, J.M., et al. 2010. Dietary modulation of oxidative stress in chronic obstructive pulmonary disease patients. Free Radic Res 44:1296-1303.

20. 1994. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330:1029-1035.

21. Halliwell, B. 2000. The antioxidant paradox. Lancet 355:1179-1180.

22. Halliwell, B. 2013. The antioxidant paradox: less paradoxical now? Br J Clin Pharmacol 75:637-644.

23. Carr, A., and Frei, B. 1999. Does vitamin C act as a prooxidant under physiological conditions? FASEB J 13:1007- 1024. 

Topics

COPD
Oxidative stress and Oxidants/Antioxidants and Free Radicals

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PVRI Chronicle Vol 2: Issue 1 cover image

January 2015

PVRI Chronicle Vol 2: Issue 1

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