**1. Introduction**

#### **1.1. Age-related macular degeneration**

Age-related macular degeneration (AMD) is a progressive retinal degeneration that is untreatable in up to 90% of patients and is the leading cause of blindness in the elderly worldwide [1]. Although much effort is invested in understanding this condition, there is neither a cure nor a way to prevent it, and treatment options are very limited. AMD affects 30% of people age 70 or older, and 60 million people worldwide are affected. Over 10 million people are affected in the United States and it is estimated that more than 300,000 new cases are diagnosed annually [2-4]. Since persons over 60 represent the fastest growing segment of the population, AMD will remain a significant public health problem for the foreseeable future [5,6].

AMD is a multifactorial disease with age, systemic health, genetic and environmental risk factors influencing disease progression [7, 8]. The most important pathogenic factors leading up to AMD include oxidative stress, inflammation, and local production of angiogenic factors [9]. A substantial body of literature suggests a role for oxidant injury to the RPE and local inflammation as putative mechanisms in the pathogenesis of AMD [10-12]. However, to date, little is known about the molecular signal(s) linking oxidation to inflammation in this lateonset disease.

In AMD loss or dysfunction of retinal photoreceptors is the ultimate cause of vision loss. However, the initial pathogenic target of AMD is the retinal pigment epithelium (RPE), Brusch's membrane (BrM), and choriochapillaris [13,14]. Clinical manifestations of AMD may present in early or a late form [15]. In early AMD (commonly known as dry degeneration) (Fig. 1B), variuos lipic-derived and protein-rich extracellular deposits, known as drusen, accumu‐

© 2013 Marin-Castaño; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

late under the RPE (Fig. 2) [14-16]. Ultimately, early AMD can progress to the late form of the disease; geographic atrophy (commonly known as advanced dry AMD) (Fig. 1C) or neovas‐ cular AMD (commonly known as wet or exudative AMD) (Fig. 1D). Geographic atrophy is characterized by death of RPE and photoreceptors (Fig. 1C) [14,15].

**2. The outer retina and choroid**

impaired [14,19].

pathology.

AMD.

As mentioned above, the pathology at the RPE/choroid interface, which includes deposition of extracellular material between the RPE and BrM, is what both AMD forms have in common. BrM undergoes several biochemical and anatomical changes with aging, including collage‐ nous thickening, calcification, and lipid infiltration, in the absence of apparent retinal dys‐ function [17,18]. The accumulation of specific deposits under the RPE is the hallmark histopathological feature of eyes with early AMD, when visual function is still not irreversibly

Cigarette Smoking and Hypertension Two Risk Factors for Age-Related Macular Degeneration

http://dx.doi.org/10.5772/53958

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The RPE is a monolayer of hexagonally arranged, highly pigmented cells, located between the neural retina and the choroid, and forming part of the blood-retina barrier (Fig. 3). Its many functions include; the absorption of light that did not get captured by the photoreceptor outer segment pigments; epithelial transport of molecules (nutrients, ions, water, and metabolites) between the subretinal space and the choroidal blood supply; spatial ion buffering; reisomerization of the chromophore 11-cis-retinal from all-trans retinal; the daily removal of photoreceptor outer segments by phagocytosis; the secretion of molecules such as growth factors, proteases, and others that control the stability of the photoreceptor cells, BrM and the choroid; and finally, the modulation of the immune response, since the RPE participates in control of the immune privilege in the healthy eye or the mounting of an immune response in the diseased eye [20]. Abnormalities in any of these processes might participate in RPE cell

**Figure 3.** Schematic image of the photoreceptors-RPE-Bruch's membrane-choriocapillaris interface and drusen in

BrM occupies a crucial interface between the RPE and choroid and contains the basement membrane of both the RPE and choroid (Fig. 3). BrM is traditionally considered to be a fivelayered stratified extracellular matrix that provides structural support to the overlying RPE and retina [6,18,21]. BrM also provides a semipermeable filtration barrier through which major metabolic exchange takes place between the RPE and the choriocapillaris. In the center of BrM

**Figure 1.** Fundus Photographs in health, early age-related macular degeneration (AMD), late forms of atrophic AMD and neovascular AMD. The ocular fundus of a healthy eye, showing normal pigmentation and retinal blood vessels (A). Drusen (thick arrows), seen as multiple discrete round yellow sub-retinal pigment epithelium (RPE) deposits, are the first sign of early AMD (B). Atrophic AMD (C) is characterized by a window defect (thin arrows) with loss of RPE and overlying photoreceptors. Neovascular AMD (D) is characterized by choroidal neovascularization (CNV), which is prone to fluid exudation, hemorrhage, and fibrosis. The late-stage dry form of AMD, known as geographic atrophy. Note large regions of depigmentation, especially in the macula, which is at the center of the image.(C) In wet AMD, leaky blood vessels from the choroid invade the overlying retina.

Neovascular AMD is characterized by the growth of new abnormal blood vessels, with leaky walls, under the RPE from the subjacent choroid, resulting in choroidal neovascularization (CNV) and subsequent dysfunction or death of the overlying neurosensory retina [14,15]. Neovascular AMD progresses much more rapidly than early AMD and leads to a greater loss of central vision. What both forms have in common, however, is pathology at the RPE/choroid interface, which includes a thickening of BrM, due to the deposition of extracellular material between the RPE and BrM (sub-RPE deposits and drusen) (Fig. 2). This review will focus on the pathobiology of the early AMD by exploring the role of cigarette smoking and hypertension in the onset and development of the disease.

**Figure 2.** Schematic image of the RPE-Bruch's membrane-choriocapillaris interface in AMD. Basal laminar deposits (BLD; \*\*) appear between the RPE cell and the RPE basement membrane, while basal linear deposits (BlinD; \*) localize at the inner collagenous layer beneath the RPE basement membrane. Arrowhead indicates endothelial cell basement membrane.
