The Pathophysiology of Cigarette Smoking and Age-Related Macular Degeneration

  • S.S. Ni Dhubhghaill
  • M.T. Cahill
  • M. Campbell
  • L. Cassidy
  • M.M. Humphries
  • P. Humphries
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 664)


Age-related macular degeneration (AMD) is the most common form of visual impairment, in people over 65, in the Western world. AMD is a multifactorial disease with genetic and environmental factors influencing disease progression. Cigarette smoking is the most significant environmental influence with an estimated increase in risk of 2- to 4-fold. Smoke-induced damage in AMD is mediated through direct oxidation, depletion of antioxidant protection, immune system activation and atherosclerotic vascular changes. Moreover, cigarette smoke induces angiogenesis promoting choroidal neovascularisation and progression to neovascular AMD. Further investigation into the effects of cigarette smoke through in vitro and in vivo experimentation will provide a greater insight into the pathogenesis of age-related macular degeneration.


Cigarette Smoke Retinal Pigment Epithelium Retinal Pigment Epithelium Cell Cigarette Smoke Exposure Macular Pigment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work is supported by the Research Foundation of the Royal Victoria Eye and Ear Hospital, Dublin and the Irish Research Council for Science Engineering and Technology (IRCSET).


  1. AREDS (2000) The age-related eye disease study: a clinical trial of zinc and antioxidants – AREDS report no. 2. J Nutr 130(5S Suppl):1516S–1519SGoogle Scholar
  2. Alberg AJ (2002) The influence of cigarette smoking on circulating concentrations of antioxidant micronutrients. Toxicology 180:121–137CrossRefPubMedGoogle Scholar
  3. Ambrose JA, Barua RS (2004) The pathophysiology of cigarette smoking and cardiovascular disease. J Am Coll Cardiol 43:1731–1737CrossRefPubMedGoogle Scholar
  4. Anderson DH, Mullins RF, Hageman GS et al (2002) A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 134:411–431CrossRefPubMedGoogle Scholar
  5. Beatty S et al (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 45(2):115–134CrossRefPubMedGoogle Scholar
  6. Bernhard D, Rossmann A, Henderson B et al (2006) Increased serum cadmium and strontium levels in young smokers: effects on arterial endothelial cell gene transcription. Arterioscler Thromb Vasc Biol 26:833–838CrossRefPubMedGoogle Scholar
  7. Bernhard D, Rossmann A, Wick G (2005) Metals in cigarette smoke. IUBMB Life 57(12):805–809CrossRefPubMedGoogle Scholar
  8. Bettman JW, Fellows V, Chao P (1958) The effect of cigarette smoking on the intraocular circulation. AMA Arch Ophthalmol 59(4):481–488PubMedGoogle Scholar
  9. Brogan AP, Dickerson TJ et al (2005) Altered retinoid homeostasis catalyzed by a nicotine metabolite: implications in macular degeneration and normal development. PNAS 102(30):10433–10438CrossRefPubMedGoogle Scholar
  10. Bruno RS, Traber MG (2006) Vitamin E biokinetics, oxidative stress and cigarette smoking. Pathophysiology 13:143–149CrossRefPubMedGoogle Scholar
  11. Cai J, Nelson KC et al (2000) Oxidative damage and protection of the RPE. Prog Eye Res 19(2):205–221CrossRefGoogle Scholar
  12. Canter JA, Olson LM, Spencer K et al (2008) Mitochondrial DNA polymorphism A4917G is independently associated with age-related macular degeneration. PLoS ONE 3(5):e2091CrossRefPubMedGoogle Scholar
  13. Chakravarthy U, Augood C, Bentham GC et al (2007) Cigarette smoking and age-related macular degeneration in the EUREYE study. Ophthalmology 114(6):1157–1163CrossRefPubMedGoogle Scholar
  14. Chow CK, Thacker RR, Changchit C et al (1986) Lower levels of vitamin C and carotenes in plasma of cigarette smokers. J Am Coll Nutr 5(3):305–312PubMedGoogle Scholar
  15. Church DF, Pryor WA (1985) Free-radical chemistry of cigarette smoke and its toxicological implications. Environ Health Perspect 64:111–126CrossRefPubMedGoogle Scholar
  16. Conklin BS, Zhao W et al (2002) Nicotine and cotinine up-regulate vascular endothelial growth factor expression in endothelial cells. Am J Pathol 160(2):413–418PubMedGoogle Scholar
  17. Donoso LA et al (2006) The role of inflammation in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 51(2):137–152CrossRefPubMedGoogle Scholar
  18. Edwards AO, Malek G (2007) Molecular genetics of AMD and current animal models. Angiogenesis 10:119–132CrossRefPubMedGoogle Scholar
  19. Eric JC, Good JA, Butz JA et al (2007) Urinary cadmium and age-related macular degeneration. Am J Ophthalmol 144(3):414–418CrossRefGoogle Scholar
  20. Espinosa-Heidmann DG, Suner IJ et al (2003) Macrophage depletion diminishes lesion size and severity in experimental choroidal neovascularisation. IOVS 44:3586–3592Google Scholar
  21. Espinosa-Heidmann DG, Suner IJ et al (2006) Cigarette smoke-related oxidants and the development of sub-RPE deposits in an experimental animal model of dry AMD. IOVS 47:729–737Google Scholar
  22. Faroon O, Roney N, Taylor J et al (2008) Acrolein environmental levels and potential for human exposure. Toxicol Ind Health 24:543CrossRefPubMedGoogle Scholar
  23. Frei B, Forte TM et al (1991) Gas phase oxidants of cigarette smoke induce lipid peroxidation and changes in lipoprotein properties in human blood plasma. Biochem J 277:133–138PubMedGoogle Scholar
  24. Friedman E (2000) The role of the atherosclerotic process in the pathogenesis of age-related macular degeneration. Am J Ophthalmol 130(5):658–663CrossRefPubMedGoogle Scholar
  25. Friedman E (2004) Update of the vascular model of AMD. Br J Ophthalmol 88:160–161CrossRefGoogle Scholar
  26. Fujihara M, Nagai N, Sussan T et al (2008) Chronic cigarette smoke causes oxidative damage and apoptosis to retinal pigmented epithelial cells in mice. PLoS ONE 3(9):e3119CrossRefPubMedGoogle Scholar
  27. Gehrs KM (2006) Age-related macular degeneration – emerging pathogenic and therapeutic concepts. Ann Med 38:450–471CrossRefPubMedGoogle Scholar
  28. Gold B, Merriam JE, Zernant J et al (2006) Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 38(4):458–462CrossRefPubMedGoogle Scholar
  29. Haines JL et al (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308:419–421CrossRefPubMedGoogle Scholar
  30. Hammond BR, Wooten BR, Snodderly DM (1996) Cigarette smoking and retinal carotenoids: implications for age-related macular degeneration. Vision Res 36(18):3003–3009CrossRefPubMedGoogle Scholar
  31. Heeschen C, Jang JJ et al (2001) Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med 7(7):833–839CrossRefPubMedGoogle Scholar
  32. Hoffmann D, Djordjevic MV, Hoffmann I (1997) The changing cigarette. Prev Med 26:427–434CrossRefPubMedGoogle Scholar
  33. Hurley SF, Matthews JP, Guymer RH (2008) Cost-effectiveness of smoking cessation to prevent age-related macular degeneration. Cost Eff Resour Alloc 6(18):1–10Google Scholar
  34. Jia L, Liu Z et al (2007) Acrolein, a toxicant in cigarette smoke, causes oxidative damage and mitochondrial dysfunction in RPE cells: protection by (R)-a-Lipoic acid. IOVS 48:339–348Google Scholar
  35. Kew RR et al (1985) Cigarette smoke can activate the alternative pathway in vitro by modifying the third component of complement. J Clin Invest 75:1000–1007CrossRefPubMedGoogle Scholar
  36. Khan JC et al (2006) Smoking and age-related macular degeneration: the number of pack years of cigarette smoking is a major determinant of risk for both geographic atrophy and choroidal neovascularization. Br J Ophthalmol 90:75–80CrossRefPubMedGoogle Scholar
  37. Kirkham PA, Spooner G et al (2003) Cigarette smoke triggers macrophage adhesion and activation: role of lipid peroxidation products and scavenger receptor. Free Radic Biol Med 35(7):697–710CrossRefPubMedGoogle Scholar
  38. Klein R (1997) The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 104:7–21PubMedGoogle Scholar
  39. Klein R (2007) Overview of progress in the epidemiology of age-related macular degeneration. Ophthalm Epidem 14(4):184–187CrossRefGoogle Scholar
  40. Loane E, Kelliher C, Beatty S et al (2008) The rational and evidence base for a protective role of macular pigment in age-related maculopathy. Br J Ophthalmol 92(9):1163–1168CrossRefPubMedGoogle Scholar
  41. Lois N, Abdelkader E, Reglitz K et al (2008) Environmental tobacco smoke exposure and eye disease. Br J Ophthalmol 92:1304–1310CrossRefPubMedGoogle Scholar
  42. Mahfouz MM, Hulea SA, Kummerow FA (1995) Cigarette smoke increases cholesterol oxidation and lipid peroxidation of low-density lipoprotein and decreases its binding to the hepatic receptor in vitro. J Environ Pathol Toxicol Oncol 14(3–4):181–192PubMedGoogle Scholar
  43. Melkonian G, Le C et al (1999) Normal patterns of angiogenesis and extracellular matrix deposition in chick chorioallantoic membranes are disupted by mainstream and sidestream smoke. Toxicol Appl Pharmacol 163:26–37CrossRefGoogle Scholar
  44. Mitchell P, Wang JJ et al (2002) Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 120(10):1357–1363PubMedGoogle Scholar
  45. Moriarty SE, Shah JH, Lynn M et al (2003) Oxidation of glutathione and cysteine in human plasma associated with smoking. Free Radic Biol Med 35(12):1582–1588CrossRefPubMedGoogle Scholar
  46. O’Connell E, Neelam K, Nolan J et al (2006) Macular carotenoids and age-related maculopathy. Ann Acad Med Singapore 35(11):821–830PubMedGoogle Scholar
  47. Panda K, Chattopadhyay R et al (1999) Vitamin C prevents cigarette smoke induced oxidative damage of proteins and increased proteolysis. Free Radic Biol Med 27(9/10):1064–1079CrossRefPubMedGoogle Scholar
  48. Panda K, Chattopadhyay R et al (2000) Vitamin C prevents cigarette smoke-induced oxidative damage in vivo. Free Radic Biol Med 29(2):115–124CrossRefPubMedGoogle Scholar
  49. Patton WP, Routledge MN et al (2002) Retinal pigment epithelial cell DNA is damaged by exposure to benzo[a]pyrene, a constituent of cigarette smoke. Exp Eye Res 74:513–522CrossRefPubMedGoogle Scholar
  50. Schmidt-Erfurth UM (2007) Management of neovascular age-related macular degeneration. Prog Ret Eye Res 26:437–451CrossRefGoogle Scholar
  51. Sharma A, Neekhra A, Gramajo AL et al (2008) Effects of Benzo(e)Pyrene, a toxic component of cigarette smoke, on human retinal pigment epithelial cells in vitro. Invest Ophthalmol Vis Sci 49:5111–5117CrossRefPubMedGoogle Scholar
  52. Solberg Y et al (1998) The association between cigarette smoking and ocular diseases. Surv Ophthalmol 42(6):535–547CrossRefPubMedGoogle Scholar
  53. Suner IJ, Espinosa-Heidmann DG et al (2004) Nicotine increases size and severity of experimental choroidal neovascularization. IOVS 45:311–317Google Scholar
  54. Thornton J et al (2005) Smoking and age-related macular degeneration: a review of association. Eye 19:935–944CrossRefPubMedGoogle Scholar
  55. Tonga AR, Latina V, Orlando R et al (2008) Cigarette smoke inhibits adenine nucleotide hydrolysis by human platelets. Platelets 19(7):537–542CrossRefGoogle Scholar
  56. U.S. Department of Health and Human services CfDCaP, National Centre for Chronic Disease Prevention and Health Promotion, and Office on Smoking and Health (2004) The health consequences of smoking; a report of the Surgeon General Atlanta, GAGoogle Scholar
  57. Van der Vaart H, Timens W, Ten Hacken NHT (2004) Acute effects of cigarette smoke on inflammation and oxidative stress: a review. Thorax 59:713–721CrossRefPubMedGoogle Scholar
  58. Walters M, Paul-Clark MJ et al (2005) Cigarette smoke activates human monocytes by an oxidant-AP-1 signaling pathway: implications for steroid resistance. Mol Pharmacol 68:1343–1353CrossRefPubMedGoogle Scholar
  59. Wills NK, Sadagopa Ramanujam VM, Chang J et al (2008) Cadmium accumulation in the human retina: effects of age, gender, and cellular toxicity. Exp Eye Res 86:41–51CrossRefPubMedGoogle Scholar
  60. Yamaguchi Y, Nasu F et al (2006) Oxidants in the gas phase of cigarette smoke pass through the lung alveolar wall and raise systemic oxidative stress. J Pharmacol Sci 103:275–282CrossRefGoogle Scholar
  61. Yanbaeva DG, Dentener MA, Creutzberg EC et al (2007) Systemic effects of smoking. Chest 131(5):1557–1566CrossRefPubMedGoogle Scholar
  62. Yates JRW, Sepp T et al (2007) Complement C3 variant and the risk of age-related macular degeneration. NEJM 357:553–561CrossRefPubMedGoogle Scholar
  63. Zhu B, Parmley WW (1995) Hemodynamic and vascular effects of active and passive smoking. Am Heart J 130:1270–1275CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • S.S. Ni Dhubhghaill
    • 1
  • M.T. Cahill
    • 1
  • M. Campbell
    • 1
  • L. Cassidy
    • 1
  • M.M. Humphries
    • 1
  • P. Humphries
    • 1
  1. 1.The Ocular Genetics Unit, Department of GeneticsTrinity College DublinDublin 2Ireland

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