Figure 3.5  Electron microscopy of normal human Bruch’s membrane, showing that the elastic layer becomes less porous and thicker from the fovea to the equator.

amino acids in the macular area. The elastic layer becomes basophilic; the elastic fibers increase in number and become more electron-dense. The BM also undergoes calcification and fragmentation, causing the membrane to lose its elasticity and become more brittle. The degree of thinning, calcification, and fragmentation of the elastic layer at the macula corresponds spatially to the distribution of the majority of macular lesions associated with age-related macular degeneration (Figure 3.5), explaining the preponderance of neovascular lesions at the macula.12 This may explain in part the fact that serum elastin-derived peptides increase with severity of age-related macular degeneration.13 Elastin fragments are also shown to increase choroidal endothelial cell migration, indicating that both local and systemic abnormalities in elastin physiology may be involved in the pathogenesis of choroidal neovascularization.

An increase in the content and structure of glycosaminoglycans (GAG) in BM has been identified. The increased volume of GAG may be partially responsible for the altered metabolism of the collagens and the resultant increased negative field may also contribute to the decreased filtration across the BM. An increased proportion of heparan sulfate in the basement membranes of the BM and simultaneous decrease in proteoglycan filaments containing chondroitin sulfate and dermatan sulfate associated with the collagen fibrils have been noted.

MATRIX METALLOPROTEINASES

Matrix metalloproteinases (MMPs) are required by BM for ECM remodeling, protein processing, and angiogenesis. The age-related increased collagen content, the release of reactive oxygen radicals by the lipid-laden BM, and the presence of inflammatory cytokines, cellular transformation, and growth hormones may upregulate these enzymes, especially MMP-2 and MMP-9. Plasma MMP-9 levels have been found to be approximately threefold higher than controls, while plasma MMP-2 did not alter significantly between disease and controls.14 The source of increased MMP-9 in the circulation in age-related macular degeneration subjects remains unclear.

One of the endogenous tissue inhibitors of MMPs (TIMPs) regulates the activation of MMPs and also has other independent actions. Of the four TIMPs characterized to date, TIMP-3 is the only member found exclusively in ECM, explaining the presence of TIMP-3 in the BM. In addition, it binds tightly to sulfated GAGs. Western blotting and quantitative reverse zymography have demonstrated an age-related increase in TIMP-3 in BM and its concentration is shown to correlate with the amount of ECM and the quantity of drusen.15 In BM, TIMP-3 controls ECM turnover, limits neovascularization, and may play a role in apoptosis. Mutations of TIMP-3 are associated with Sorsby’s fundus

Figure 3.6  Fundus appearance of a patient with Sorsby’s fundus dystrophy.

dystrophy (Figure 3.6), suggesting that mutant TIMP-3 may result in aberrant protein interaction and increased cell adhesiveness, which may cause defective turnover of the BM.16

PHARMACOTHERAPY IMPLICATIONS

It is unclear whether the vitreous is a friend or a foe. However, in many circumstances, a controlled separation of the posterior vitreous base and the retina is beneficial. The key here is “controlled” and ideally noninvasive separation. The pathophysiology role in the changes of blood flow in retinal vascular diseases is complex: it remains unclear whether the vascular dilatation commonly seen in these diseases is a beneficial compensation or a cause of further vascular damage. Many drugs can modify the vascular caliber: the therapeutic potential is vast.

The controversy of macular pigments remains unresolved; laboratory evidence does not always translate to clinical benefit. The AgeRelated Eye Disease Study (AREDS 2) will give us further insight. Genetic changes of phototransduction are often associated with retinal degeneration, the ability to target and modify the visual cycle or, by reducing apoptosis in reducing cell death, can be potentially useful in treating these diseases by modifying the genetic defect itself.

The abnormal turnover of the ECM, especially in the BM, is clearly implicated in the pathophysiology of age-related macular degeneration. Controlling this aberration will be potentially rewarding.

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