Neovascular AMD typically occurs in areas of atrophic AMD and is characterised by the infiltration of choroidal neovascularisation (CNV) through Bruch’s membrane towards the neural retina. These new choroidal vessels are fragile and may result in multiple complications – haemorrhage, retinal detachment, retinal atrophy and disciform scarring resulting in rapid visual loss (Schmidt-Erfurth 2007). CNV is likely a response to tissue injury and similar in nature to the granular tissue of the generalised wound healing response (Donoso et al. 2006).

50.2 Cigarette Smoking as a Risk Factor for AMD

50.2.1 AMD and Cigarette Smoke

The aetiology of AMD is complex, involving interactions between genetic and environmental risk factors. Cigarette smoking is the most significant environmental risk factor contributing to the development of AMD (Thornton et al. 2005). Smoking increases the risk of developing AMD 2- to 4-fold and passive smokers are also at an increased risk (Lois et al. 2008). Cigarette smoke further affects AMD by promoting progression from atrophic to neovascular AMD (Chakravarthy et al. 2007). This may occur up to ten years earlier in smokers than in non-smokers (Mitchell et al. 2002). Cessation reduces the risk of developing AMD and progression to neovascular AMD (Khan et al. 2006) and for every 1,000 smokers that successfully quit, there would be 48 fewer cases of macular degeneration with 12 fewer cases of blindness (Hurley et al. 2008).

50.2.2 Cigarette Smoke Constituents

Cigarette smoke is separated into two phases, a gas phase and a tar phase based on passage through a standard filter (Church and Pryor 1985). With each cigarette, smokers consume over 4,000 different compounds (Hoffmann et al. 1997). Therefore it is unlikely that cigarette smoke exerts its pathological effects through a single biochemical pathway. Though the consequences of ocular exposure to the full range of cigarette smoke constituents are not yet known, it is thought that oxidative damage, vascular and inflammatory changes play key roles in the pathogenesis of AMD (U.S. Department of Health and Human services CfDCaP et al. 2004).

50.3 Oxidative Stress

50.3.1 Oxidative Damage in AMD

The RPE layer is exposed to high levels of oxidative damage from both the retina and the systemic circulation (Beatty et al. 2000). It has been hypothesized that

cumulative oxidative damage to the RPE contributes to the development and progression of atrophic AMD (Beatty et al. 2000; Cai et al. 2000) and without the metabolic support of the RPE, overlying photoreceptors undergo apoptosis. This hypothesis is supported clinically by the modest benefits of antioxidant therapy in dry AMD (AREDS 2000).

Two single nucleotide polymorphisms (SNPs) Loc387715/ARMS2 and A4917G in mitochondrial DNA have been linked to AMD (Canter et al. 2008). It is plausible that the structural protein changes conferred by these SNPs impair the ability of the mitochondrion to process oxidative stresses. Thus, oxidative damage to mitochondrial DNA leading to RPE apoptosis may be a key step in the initiation of AMD (Sharma et al. 2008).

Mice exposed to chronic cigarette smoke display RPE apoptosis and Bruch membrane alterations which can be attributed to oxidative damage (Fujihara et al. 2008). Moreover, chronic smoke exposure in mice yields basal laminar deposits reminiscent of drusen (Espinosa-Heidmann et al. 2006).

50.3.2 Reactive Oxygen Species in Cigarette Smoke

Cigarette smoke contains >1015 free radicals per inhalation (Church and Pryor 1985) and numerous other chemicals that may be metabolized into reactive oxygen intermediates. These oxidants in cigarette smoke can pass through the alveolar walls and enter the circulation (Yamaguchi et al. 2006). Plasma markers of lipid peroxidation are increased after smoking confirming that smoke derived radicals pass into the circulation with the potential to exert widespread systemic effects (Frei et al. 1991).

50.3.3 Acrolein-Induced Oxidative Stress

In addition to directly generating short-lived reactive oxygen species, cigarette smoke contains a number of more stable components that inflict oxidative damage. Acrolein is an unsaturated aldehyde found in the gas phase of cigarette smoke in quantities of 3–220 μg per cigarette (Faroon et al. 2008). It is capable of exerting an oxidant-mediated damage, inducing protein modifications and promoting the formation of advanced glycation end-products (AGEPs) and advanced lipid end products (ALEPs) (Kirkham et al. 2003). RPE cells exposed to acrolein show a decrease in viability and mitochondrial membrane potential due to oxidative stress (Jia et al. 2007).

50.3.4 Cadmium-Induced Oxidative Stress

In humans, the main source of cadmium intake is through cigarette smoke (Bernhard et al. 2005). Plasma and retinal levels of cadmium are significantly higher in