Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Aug 2;91(16):7688–7692. doi: 10.1073/pnas.91.16.7688

Vitamin C prevents cigarette smoke-induced leukocyte aggregation and adhesion to endothelium in vivo.

H A Lehr 1, B Frei 1, K E Arfors 1
PMCID: PMC44467  PMID: 7519784

Abstract

A common feature of cigarette-smoke (CS)-associated diseases such as atherosclerosis and pulmonary emphysema is the activation, aggregation, and adhesion of leukocytes to micro- and macrovascular endothelium. A previous study, using a skinfold chamber model for intravital fluorescence microscopy in awake hamsters, has shown that exposure of hamsters to the smoke generated by one research cigarette elicits the adhesion of fluorescently labeled leukocytes to the endothelium of arterioles and small venules. By the combined use of intravital microscopy and scanning electron microscopy, we now demonstrate in the same animal model that (i) CS-induced leukocyte adhesion is not confined to the microcirculation, but that leukocytes also adhere singly and in clusters to the aortic endothelium; (ii) CS induces the formation in the bloodstream of aggregates between leukocytes and platelets; and (iii) CS-induced leukocyte adhesion to micro- and macrovascular endothelium and leukocyte-platelet aggregate formation are almost entirely prevented by dietary or intravenous pretreatment with the water-soluble antioxidant vitamin C (venules, 21.4 +/- 11.0 vs. 149.6 +/- 38.7 leukocytes per mm2, P < 0.01; arterioles, 8.5 +/- 4.2 vs. 54.3 +/- 21.6 leukocytes per mm2, P < 0.01; aortas, 0.8 +/- 0.4 vs. 12.4 +/- 5.6 leukocytes per mm2, P < 0.01; means +/- SD of n = 7 animals, 15 min after CS exposure). No inhibitory effect was observed by pretreatment of the animals with the lipid-soluble antioxidants vitamin E or probucol. The protective effects of vitamin C on CS-induced leukocyte adhesion and aggregation were seen at vitamin C plasma levels (55.6 +/- 22.2 microM, n = 7) that can easily be reached in humans by dietary means or supplementation, suggesting that vitamin C effectively contributes to protection from CS-associated cardiovascular and pulmonary diseases in humans.

Full text

PDF
7689

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson R. Assessment of the roles of vitamin C, vitamin E, and beta-carotene in the modulation of oxidant stress mediated by cigarette smoke-activated phagocytes. Am J Clin Nutr. 1991 Jan;53(1 Suppl):358S–361S. doi: 10.1093/ajcn/53.1.358S. [DOI] [PubMed] [Google Scholar]
  2. Benowitz N. L. Drug therapy. Pharmacologic aspects of cigarette smoking and nicotine addition. N Engl J Med. 1988 Nov 17;319(20):1318–1330. doi: 10.1056/NEJM198811173192005. [DOI] [PubMed] [Google Scholar]
  3. Boogaerts M. A., Van de Broeck J., Deckmyn H., Roelant C., Vermylen J., Verwilghen R. L. Protective effect of vitamin E on immune triggered, granulocyte mediated endothelial injury. Thromb Haemost. 1984 Feb 28;51(1):89–92. [PubMed] [Google Scholar]
  4. Bosken C. H., Doerschuk C. M., English D., Hogg J. C. Neutrophil kinetics during active cigarette smoking in rabbits. J Appl Physiol (1985) 1991 Aug;71(2):630–637. doi: 10.1152/jappl.1991.71.2.630. [DOI] [PubMed] [Google Scholar]
  5. Carew T. E., Schwenke D. C., Steinberg D. Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7725–7729. doi: 10.1073/pnas.84.21.7725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Church D. F., Pryor W. A. Free-radical chemistry of cigarette smoke and its toxicological implications. Environ Health Perspect. 1985 Dec;64:111–126. doi: 10.1289/ehp.8564111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Drost E. M., Selby C., Bridgeman M. M., MacNee W. Decreased leukocyte deformability after acute cigarette smoking in humans. Am Rev Respir Dis. 1993 Nov;148(5):1277–1283. doi: 10.1164/ajrccm/148.5.1277. [DOI] [PubMed] [Google Scholar]
  8. Enstrom J. E., Kanim L. E., Klein M. A. Vitamin C intake and mortality among a sample of the United States population. Epidemiology. 1992 May;3(3):194–202. doi: 10.1097/00001648-199205000-00003. [DOI] [PubMed] [Google Scholar]
  9. Esterbauer H., Dieber-Rotheneder M., Striegl G., Waeg G. Role of vitamin E in preventing the oxidation of low-density lipoprotein. Am J Clin Nutr. 1991 Jan;53(1 Suppl):314S–321S. doi: 10.1093/ajcn/53.1.314S. [DOI] [PubMed] [Google Scholar]
  10. Frank E. Benefits of stopping smoking. West J Med. 1993 Jul;159(1):83–86. [PMC free article] [PubMed] [Google Scholar]
  11. Frei B., England L., Ames B. N. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6377–6381. doi: 10.1073/pnas.86.16.6377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Frei B., Forte T. M., Ames B. N., Cross C. E. Gas phase oxidants of cigarette smoke induce lipid peroxidation and changes in lipoprotein properties in human blood plasma. Protective effects of ascorbic acid. Biochem J. 1991 Jul 1;277(Pt 1):133–138. doi: 10.1042/bj2770133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Frei B., Stocker R., Ames B. N. Antioxidant defenses and lipid peroxidation in human blood plasma. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9748–9752. doi: 10.1073/pnas.85.24.9748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gey K. F., Moser U. K., Jordan P., Stähelin H. B., Eichholzer M., Lüdin E. Increased risk of cardiovascular disease at suboptimal plasma concentrations of essential antioxidants: an epidemiological update with special attention to carotene and vitamin C. Am J Clin Nutr. 1993 May;57(5 Suppl):787S–797S. doi: 10.1093/ajcn/57.5.787S. [DOI] [PubMed] [Google Scholar]
  15. Halliwell B., Wasil M., Grootveld M. Biologically significant scavenging of the myeloperoxidase-derived oxidant hypochlorous acid by ascorbic acid. Implications for antioxidant protection in the inflamed rheumatoid joint. FEBS Lett. 1987 Mar 9;213(1):15–17. doi: 10.1016/0014-5793(87)81456-4. [DOI] [PubMed] [Google Scholar]
  16. Imaizumi T., Satoh K., Yoshida H., Kawamura Y., Hiramoto M., Takamatsu S. Effect of cigarette smoking on the levels of platelet-activating factor-like lipid(s) in plasma lipoproteins. Atherosclerosis. 1991 Mar;87(1):47–55. doi: 10.1016/0021-9150(91)90231-q. [DOI] [PubMed] [Google Scholar]
  17. Janoff A. Elastases and emphysema. Current assessment of the protease-antiprotease hypothesis. Am Rev Respir Dis. 1985 Aug;132(2):417–433. doi: 10.1164/arrd.1985.132.2.417. [DOI] [PubMed] [Google Scholar]
  18. Jonas E., Dwenger A., Hager A. In vitro effect of ascorbic acid on neutrophil-endothelial cell interaction. J Biolumin Chemilumin. 1993 Jan-Feb;8(1):15–20. doi: 10.1002/bio.1170080104. [DOI] [PubMed] [Google Scholar]
  19. Kilburn K. H., McKenzie W. Leukocyte recruitment to airways by cigarette smoke and particle phase in contrast to cytotoxicity of vapor. Science. 1975 Aug 22;189(4203):634–637. doi: 10.1126/science.1162344. [DOI] [PubMed] [Google Scholar]
  20. Klut M. E., Doerschuk C. M., Van Eeden S. F., Burns A. R., Hogg J. C. Activation of neutrophils within pulmonary microvessels of rabbits exposed to cigarette smoke. Am J Respir Cell Mol Biol. 1993 Jul;9(1):82–89. doi: 10.1165/ajrcmb/9.1.82. [DOI] [PubMed] [Google Scholar]
  21. Lehr H. A., Arfors K. E. Mechanisms of tissue damage by leukocytes. Curr Opin Hematol. 1994 Jan;1(1):92–99. [PubMed] [Google Scholar]
  22. Lehr H. A., Hübner C., Finckh B., Angermüller S., Nolte D., Beisiegel U., Kohlschütter A., Messmer K. Role of leukotrienes in leukocyte adhesion following systemic administration of oxidatively modified human low density lipoprotein in hamsters. J Clin Invest. 1991 Jul;88(1):9–14. doi: 10.1172/JCI115309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lehr H. A., Kress E., Menger M. D., Friedl H. P., Hübner C., Arfors K. E., Messmer K. Cigarette smoke elicits leukocyte adhesion to endothelium in hamsters: inhibition by CuZn-SOD. Free Radic Biol Med. 1993 Jun;14(6):573–581. doi: 10.1016/0891-5849(93)90138-k. [DOI] [PubMed] [Google Scholar]
  24. Ludwig P. W., Schwartz B. A., Hoidal J. R., Niewoehner D. E. Cigarette smoking causes accumulation of polymorphonuclear leukocytes in alveolar septum. Am Rev Respir Dis. 1985 Jun;131(6):828–830. doi: 10.1164/arrd.1985.131.6.828. [DOI] [PubMed] [Google Scholar]
  25. MacNee W., Wiggs B., Belzberg A. S., Hogg J. C. The effect of cigarette smoking on neutrophil kinetics in human lungs. N Engl J Med. 1989 Oct 5;321(14):924–928. doi: 10.1056/NEJM198910053211402. [DOI] [PubMed] [Google Scholar]
  26. McEver R. P. GMP-140: a receptor for neutrophils and monocytes on activated platelets and endothelium. J Cell Biochem. 1991 Feb;45(2):156–161. doi: 10.1002/jcb.240450206. [DOI] [PubMed] [Google Scholar]
  27. McLean L. R., Hagaman K. A. Effect of probucol on the physical properties of low-density lipoproteins oxidized by copper. Biochemistry. 1989 Jan 10;28(1):321–327. doi: 10.1021/bi00427a043. [DOI] [PubMed] [Google Scholar]
  28. Niewoehner D. E., Peterson F. J., Hoidal J. R. Selenium and vitamin E deficiencies do not enhance lung inflammation from cigarette smoke in the hamster. Am Rev Respir Dis. 1983 Feb;127(2):227–230. doi: 10.1164/arrd.1983.127.2.227. [DOI] [PubMed] [Google Scholar]
  29. Pacht E. R., Davis W. B. Failure of high-dose vitamin E to correct ceruloplasmin ferroxidase deficiency in cigarette smokers. Am Rev Respir Dis. 1990 Nov;142(5):1063–1067. doi: 10.1164/ajrccm/142.5.1063. [DOI] [PubMed] [Google Scholar]
  30. Patel K. D., Zimmerman G. A., Prescott S. M., McEver R. P., McIntyre T. M. Oxygen radicals induce human endothelial cells to express GMP-140 and bind neutrophils. J Cell Biol. 1991 Feb;112(4):749–759. doi: 10.1083/jcb.112.4.749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pittilo R. M., Bull H. A., Gulati S., Rowles P. M., Blow C. M., Machin S. J., Woolf N. Nicotine and cigarette smoking: effects on the ultrastructure of aortic endothelium. Int J Exp Pathol. 1990 Aug;71(4):573–586. [PMC free article] [PubMed] [Google Scholar]
  32. Pittilo R. M., Mackie I. J., Rowles P. M., Machin S. J., Woolf N. Effects of cigarette smoking on the ultrastructure of rat thoracic aorta and its ability to produce prostacyclin. Thromb Haemost. 1982 Oct 29;48(2):173–176. [PubMed] [Google Scholar]
  33. Pryor W. A., Dooley M. M., Church D. F. The inactivation of alpha-1-proteinase inhibitor by gas-phase cigarette smoke: protection by antioxidants and reducing species. Chem Biol Interact. 1986 Mar;57(3):271–283. doi: 10.1016/0009-2797(86)90002-5. [DOI] [PubMed] [Google Scholar]
  34. Pryor W. A., Prier D. G., Church D. F. Electron-spin resonance study of mainstream and sidestream cigarette smoke: nature of the free radicals in gas-phase smoke and in cigarette tar. Environ Health Perspect. 1983 Jan;47:345–355. doi: 10.1289/ehp.8347345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Riemersma R. A., Wood D. A., Macintyre C. C., Elton R. A., Gey K. F., Oliver M. F. Risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene. Lancet. 1991 Jan 5;337(8732):1–5. doi: 10.1016/0140-6736(91)93327-6. [DOI] [PubMed] [Google Scholar]
  36. Rimm E. B., Stampfer M. J., Ascherio A., Giovannucci E., Colditz G. A., Willett W. C. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993 May 20;328(20):1450–1456. doi: 10.1056/NEJM199305203282004. [DOI] [PubMed] [Google Scholar]
  37. Ross R. Rous-Whipple Award Lecture. Atherosclerosis: a defense mechanism gone awry. Am J Pathol. 1993 Oct;143(4):987–1002. [PMC free article] [PubMed] [Google Scholar]
  38. Schectman G., Byrd J. C., Gruchow H. W. The influence of smoking on vitamin C status in adults. Am J Public Health. 1989 Feb;79(2):158–162. doi: 10.2105/ajph.79.2.158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Smiley P. L., Stremler K. E., Prescott S. M., Zimmerman G. A., McIntyre T. M. Oxidatively fragmented phosphatidylcholines activate human neutrophils through the receptor for platelet-activating factor. J Biol Chem. 1991 Jun 15;266(17):11104–11110. [PubMed] [Google Scholar]
  40. Weiss S. J. Tissue destruction by neutrophils. N Engl J Med. 1989 Feb 9;320(6):365–376. doi: 10.1056/NEJM198902093200606. [DOI] [PubMed] [Google Scholar]
  41. Williams R. J., Motteram J. M., Sharp C. H., Gallagher P. J. Dietary vitamin E and the attenuation of early lesion development in modified Watanabe rabbits. Atherosclerosis. 1992 Jun;94(2-3):153–159. doi: 10.1016/0021-9150(92)90240-h. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES