50.6.2 Cigarette Smoke and Complement Pathway

Cigarette smoke can directly activate C3, a key component in the Alternative complement pathway (Kew et al. 1985) as well as reduce serum levels of CFH, a circulating inhibitor of complement activation. It is possible therefore that complement-related genetic risk factors and cigarette smoke-induced complement activation act synergistically to promote inflammation in AMD.

50.6.3 Cigarette Smoke and Other Inflammatory Mediators

Cigarette smoke is also associated with a state of systemic chronic low-grade inflammation (Yanbaeva et al. 2007). Leukocyte and neutrophil concentrations are elevated in the blood of smokers (Van der Vaart et al. 2004; Solberg et al. 1998). Human monocytes are activated by cigarette smoke in vitro through oxidant-mediated pathways (Walters et al. 2005) indicating that the oxidative stress and immunological hypostheses of AMD aetiology may not be mutually exclusive.

50.7 Vascular Changes

The vascular model of AMD provides an alternative hypothesis for the aetiology of AMD (Friedman 2000). This model postulates that the initial changes in AMD occur in the choroidal vasculature in a process analogous to atherosclerosis. Cigarette smoke exacerbates atherosclerotic changes in the coronary arteries (Ambrose and Barua 2004), oxidizes cholesterol and low-density lipoproteins (Mahfouz et al. 1995), and activates platelets promoting aggregation (Tonga et al. 2008). Smoke also induces blood vessel constriction through α-adrenergic receptor activation. In vivo, animals exposed to chronic cigarette smoke display significantly increased choroidal vascular resistance (Bettman et al. 1958). A decrease in choroidal circulation may impair the clearance of debris from the RPE and lead to the depositions in the Bruch membrane seen in AMD (Friedman 2004).

Cigarette smoke exposure significantly alters the branching pattern and extracellular matrices of proliferating vessels (Melkonian et al. 1999). These vessels were accompanied by a higher number of fibroblasts than unexposed controls. Thus smoke may further compromise the infiltrating vessels in CNV membranes.

50.8 Conclusions

Age-related macular degeneration is a disease of multifactorial aetiology with both genetic and environmental influences. Cigarette smoke is the most significant environmental factor known. This highly potent toxin causes oxidative stress, promotes inflammation and induces vascular changes. Further assessment of the

Fig. 50.1 Cigarette smoke-mediated influences in the pathophysiology of AMD

effects of smoke in vitro and in vivo is required to fully understand its role in the pathophysiology of AMD (Fig. 50.1).

Acknowledgments 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).

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