metabolism which are currently under investigation. We also looked at the effects of PUFAs on ECM expression, since they accumulate in Bruch’s membrane and subRPE deposits in ARMD. Since the promoter of ECMs lack a PPRE, it is unlikely that PUFA-ligand activated PPARs ‘directly’ stimulate ECM regulation, rather it would involve intermediary molecules such as TGFβ or PAI (plasminogen activator inhibitor), which have been shown to regulate ECM production in the lung and liver (Arteel 2008). Specifically, PAI has been shown to inhibit ECM breakdown suggesting that a potential mechanism by which PPARs influence ECM production could be through TGFβ which stimulates an increase in PAI, decreasing ECM degradation, resulting in an overall increase of ECM.

Altered activated states of the three isoforms of PPARs support the evolutionary notion of PPARs as a solution to the ‘hypoxia-lipid’ conundrum as proposed by Nunn et al. (2007) where ‘the ability to store and burn fat is essential for survival, but is a “double-edged sword”, as fats are potentially highly toxic’. Some evidence exists demonstrating PPAR-γ may be a potential player in late neovascular ARMD, in which concomitant with RPE degeneration, the underlying choriocapillaris becomes less fenestrated, impairing transport of macromolecules, such as oxygen, between the retina and choroidal blood supply. This hypoxia may in part stimulate neovascularization through VEGF. Murata and colleagues have shown that PPAR-γ not only may be a downstream inhibitor of VEGF, but also intravitreal treatment of murine eyes after laser induced CNV with synthetic agonists resulted in smaller sized lesions and less leakage compared to placebo (Murata et al. 2000). Our long term goals are to understand how dietary and or elevated locally produced lipids contribute to the pathology of sub-RPE deposit formation in ARMD. Studies on the role of the individual PPAR isoforms and their activation state following dietary insult in ARPE19, as a potential link in progression of dry ARMD, are ongoing.

Acknowledgments This work was supported by a grant from the International Retinal Research Foundation and Research to Prevent Blindness.

References

Anderson DH, Mullins RF et al (2002) A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 134(3):411–431

Anderson DH, Talaga KC et al (2004) Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Exp Eye Res 78(2): 243–256

Arteel GE (2008) New role of plasminogen activator inhibitor-1 in alcohol-induced liver injury. J Gastroenterol Hepatol 23(Suppl 1):S54–S59

Bird AC, Bressler NM et al (1995) An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol 39(5):367–374

Canter JA, Olson LM et al (2008) Mitochondrial DNA polymorphism A4917G is independently associated with age-related macular degeneration. PLoS ONE 3(5):e2091

Chawla A, Boisvert WA et al (2001) A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7(1):161–171

Chinetti G, Fruchart JC et al (2001) Peroxisome proliferator-activated receptors (PPARs): nuclear receptors with functions in the vascular wall. Z Kardiol 90(Suppl 3):125–132

Crabb JW, Miyagi M et al (2002) Drusen proteome analysis: an approach to the etiology of agerelated macular degeneration. Proc Natl Acad Sci U S A 99(23):14682–14687

Curcio CA, Millican CL (1999) Basal linear deposit and large drusen are specific for early agerelated maculopathy. Arch Ophthalmol 117(3):329–339

Curcio CA, Presley JB et al (2005) Esterified and unesterified cholesterol in drusen and basal deposits of eyes with age-related maculopathy. Exp Eye Res 81(6):731–741

Edwards AO, Ritter R 3rd et al (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308(5720):421–424

Fiotti N, Pedio M et al (2005) MMP-9 microsatellite polymorphism and susceptibility to exudative form of age-related macular degeneration. Genet Med 7(4):272–277

Green WR (1999) Histopathology of age-related macular degeneration. Mol Vis 5:27

Hageman GS, Anderson DH et al (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 102(20):7227–7232

Hageman GS, Luthert PJ et al (2001) An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 20(6):705–732

Hageman GS, Mullins RF et al (1999) Vitronectin is a constituent of ocular drusen and the vitronectin gene is expressed in human retinal pigmented epithelial cells. FASEB J 13(3):477–484 Haines JL, Hauser MA et al (2005) Complement factor H variant increases the risk of age-related

macular degeneration. Science 308(5720):419–421

Johnson LV, Leitner WP et al (2002) The Alzheimer’s A beta-peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc Natl Acad Sci U S A 99(18):11830–11835

Kersten S, Desvergne B et al (2000) Roles of PPARs in health and disease. Nature 405(6785): 421–424

Klein R, Klein BE et al (2007) Fifteen-year cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology 114(2):253–262

Klein RJ, Zeiss C et al (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308(5720):385–389

Malek G, Li CM et al (2003) Apolipoprotein B in cholesterol-containing drusen and basal deposits of human eyes with age-related maculopathy. Am J Pathol 162(2):413–425

Moore KJ, Fitzgerald ML et al (2001) Peroxisome proliferator-activated receptors in macrophage biology: friend or foe? Curr Opin Lipidol 12(5):519–527

Murata T, He S et al (2000) Peroxisome proliferator-activated receptor-gamma ligands inhibit choroidal neovascularization. Invest Ophthalmol Vis Sci 41(8):2309–2317

Nunn AV, Bell J et al (2007) The integration of lipid-sensing and anti-inflammatory effects: how the PPARs play a role in metabolic balance. Nucl Recept 5(1):1

Olefsky JM, Saltiel AR (2000) PPAR gamma and the treatment of insulin resistance. Trends Endocrinol Metab 11(9):362–368

Ross RJ, Bojanowski CM et al (2007) The LOC387715 polymorphism and age-related macular degeneration: replication in three case-control samples. Invest Ophthalmol Vis Sci 48(3): 1128–1132

Sampath H, Ntambi JM (2005) Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu Rev Nutr 25:317–340

SanGiovanni JP, Chew EY et al (2007) The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20. Arch Ophthalmol 125(5):671–679

SanGiovanni JP, Chew EY et al (2008) The relationship of dietary omega-3 long-chain polyunsaturated fatty acid intake with incident age-related macular degeneration: AREDS Report No. 23. Arch Ophthalmol 126(9):1274–1279

Schmidt S, Klaver C et al (2002) A pooled case-control study of the apolipoprotein E (APOE) gene in age-related maculopathy. Ophthalmic Genet 23(4):209–223

Yang Z, Camp NJ et al (2006) A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314(5801):992–993

Chapter 50

The Pathophysiology of Cigarette Smoking

and Age-Related Macular Degeneration

S. S. Ni Dhubhghaill, M.T. Cahill, M. Campbell, L. Cassidy, M.M. Humphries, and P. Humphries

Abstract 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.

50.1 Introduction

Age-related macular degeneration (AMD) is a progressive, degenerative eye condition affecting the central (macular) portion of the retina (Gehrs 2006), and is the leading cause of visual impairment in people over 65 in the Western world (Klein 2007). With aging populations, the prevalence and incidence of this disease are increasing, resulting in increased debilitation and social burden.

Clinically AMD may be classified as either atrophic or neovascular. Atrophic AMD is the commonest form, affecting approximately 85% of persons with AMD (Klein 1997). It is characterized by retinal pigment epithelium cell layer (RPE) abnormalities, drusen (collections of extracellular debris beneath the RPE), and in some cases retinal pigment epithelial detachment (RPED). Geographic atrophy (GA) is an advanced form of atrophic AMD involving widespread atrophy of the RPE, inducing apoptosis of overlying photoreceptors and subsequent exposure of choroidal vessels.

S.S. Ni Dhubhghaill (B)

The Ocular Genetics Unit, Department of Genetics, Trinity College Dublin, Dublin 2, Ireland e-mail: nidhubs@tcd.ie

Medicine and Biology 664, DOI 10.1007/978-1-4419-1399-9_50,C Springer Science+Business Media, LLC 2010