Age-related macular degeneration (AMD), consisting of atrophic and exudative AMD, is an idiopathic retinal degenerative disease that predominates in the elderly in the Western world as a cause of irreversible, profound vision loss.
7 Atrophic AMD, characterized by drusen formation and geographic atrophy, accounts for approximately 75% of cases. Exudative AMD is characterized by choroidal neovascularization (CNV) under the RPE and retina, with subsequent hemorrhage and retinal detachment.
8 The molecular mechanisms whereby pathogenic factors contribute to the development of AMD remain elusive. However, growing evidence indicates that inflammation contributes to disease formation. The inflammatory response evolves in the early asymptomatic and dry drusenoid stage and in the early stage of CNV.
9 Initial evidence for the role of inflammation in CNV formation is derived from anatomic studies.
10 Further support for a role of inflammation in CNV comes from macrophage depletion and knockout mouse studies. Macrophage depletion inhibits experimental CNV.
11 12 CNV induction is also markedly decreased in intercellular adhesion molecule (ICAM)-1 or CD18 (ICAM-1 receptor)-deficient mice,
13 suggesting that leukocyte infiltration plays an important role in the angiogenic reaction. Molecular evidence for the role of inflammation in drusen biogenesis, the biomarker of atrophic AMD, has recently been described by Hageman,
6 Johnson,
14 and Anderson,
15 and an inflammation hypothesis for drusen biogenesis has been proposed.
6 In this model, entrapped RPE debris between the RPE basal lamina and Bruch membrane is construed as the critical seeding event in drusen formation, triggering local upregulation of proinflammatory mediators and activation of the complement cascade. RPE cells are considered a major source of proinflammatory mediators. In vivo disruption of RPE inhibits the development of experimental autoimmune uveitis.
16 Proinflammatory cytokines, phagocytosis of oxidized photoreceptor outer segments, or complement fragments lead to the release of chemotactic cytokines such as interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, and expression of ICAM-1.
17 18 19 20 ICAM-1 expression in concert with locally released chemokines promotes extravasation of inflammatory cells into the retina.
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