**4. Hypothetical model for dry AMD and its progression to wet AMD**

Our research is based on the RPE injury hypothesis (Fig. 4). Oxidative injury-mediated non lethal RPE membrane blebbing, dysregulation of ECM turnover, inflammation, and angio‐ genesis appear to be key cellular processes that play a central role in the formation and progression of sub-RPE deposits. We postulate that the pathogenesis and progression of dry AMD is characterized by the following stages: (A) Initial RPE oxidant injury causes extrusion of cell membrane "blebs," together with decreased activity of matrix metalloproteinases (MMPs), promoting bleb accumulation under the RPE as BLD. Numerous endogenous or exogenous oxidants can induce blebbing; (B) RPE cells are subsequently stimulated to increase synthesis of MMPs and other molecules responsible for extracellular matrix turnover (i.e., producing decreased laminin and collagen), affecting both RPE basement membrane and BrM [46,53,54]. This process leads to progression of BLD into BLinD and drusen by admixture of blebs into BrM, followed by the formation of new basement membrane under the RPE to trap these deposits within BrM [55,56]. We postulate that various hormones and other plasmaderived molecules related to systemic health cofactors are implicated in this stage [57-60]. (C) Altered macrophages recruitment to sites of RPE injury and deposit formation. Macrophage recruitment may be beneficial or harmful depending upon their activation status at the time of recruitment [50,61]. Nonactivated or scavenging macrophages may remove deposits without further injury. Activated or reparative macrophages, through the release of inflam‐ matory mediators, growth factors, or other substances, may promote complications and progression to the late forms of the disease [37,50,62,37]. As discussed below, the effect of cigarette smoking and Ang II in the mentioned stages will be reviewed in depth.

portions of its basal cytoplasm into BrM [38], possibly as a mechanism for removing damaged cytosol [41] or as a byproduct of phagocytic degradation [19]. Others have postulated that drusen are formed by autolysis of the RPE, due to aberrant lysosomal enzyme activity [42], although enzyme histochemical studies failed to demonstrate the presence of lysosomal enzymes in drusen [43]. Additional mechanisms for drusen formation, including lipoidal

44 Age-Related Macular Degeneration - Etiology, Diagnosis and Management - A Glance at the Future

In the modern version, the RPE injury hypothesis proposes that deposit formation is secondary to chronic, repetitive but nonlethal RPE injury [46, 47]. Two separate phenomena must be distinguished: the injury stimulus and the cellular response. The most widely implicated injury stimuli are various oxidants, especially those induced by RPE exposure to visible light or those derived from endogenous metabolism [48,49]. More recently, inflammatory-derived injury stimuli have also become implicated, including oxidants, complement, immune complexes and factors produced by macrophages or monocyte [50-52]. Inflammatory cells might be responsible for drusen progression into CNV by secretion of growth factors and cytokines that will damage the choriocapillaris and stimulate the invasion of neovessels into the subretinal

Irrespective of the injury, this model proposes that all stimuli result in a final common pathway of cellular responses that cause the actual deposits. Cellular responses that can lead to deposit formation include RPE cell membrane blebbing and dysregulation of extracellular matrix (ECM) production and breakdown. Accumulation of sub-RPE blebbed material in the setting of imbalanced breakdown and resynthesis of basement membrane and BrM ECM is proposed to produce the various deposits of AMD. Repetitive injury ultimately can kill RPE, leading to

**4. Hypothetical model for dry AMD and its progression to wet AMD**

Our research is based on the RPE injury hypothesis (Fig. 4). Oxidative injury-mediated non lethal RPE membrane blebbing, dysregulation of ECM turnover, inflammation, and angio‐ genesis appear to be key cellular processes that play a central role in the formation and progression of sub-RPE deposits. We postulate that the pathogenesis and progression of dry AMD is characterized by the following stages: (A) Initial RPE oxidant injury causes extrusion of cell membrane "blebs," together with decreased activity of matrix metalloproteinases (MMPs), promoting bleb accumulation under the RPE as BLD. Numerous endogenous or exogenous oxidants can induce blebbing; (B) RPE cells are subsequently stimulated to increase synthesis of MMPs and other molecules responsible for extracellular matrix turnover (i.e., producing decreased laminin and collagen), affecting both RPE basement membrane and BrM [46,53,54]. This process leads to progression of BLD into BLinD and drusen by admixture of blebs into BrM, followed by the formation of new basement membrane under the RPE to trap these deposits within BrM [55,56]. We postulate that various hormones and other plasmaderived molecules related to systemic health cofactors are implicated in this stage [57-60]. (C) Altered macrophages recruitment to sites of RPE injury and deposit formation. Macrophage

degeneration of the RPE, have been proposed [44,45].

space [37,51,52].

late dry AMD [6].

**Figure 4.** Schematic drawing of the early stages of age-related macular degeneration (AMD). First stage: Oxidant in‐ jury at the retinal pigment epithelium (RPE) causes bleb formation and decreased matrix metalloproteinases (MMPs). Blebs than accumulate between the RPE and the basement membrane as basal laminar deposits (BLDs). Second stage: Increased matrix turnover characterized by increased MMPs and decreased collagens. BLDs progress into basal linear deposits (BLinDs) and drusen and are located within the inner collagenous layer of Bruchs membrane. Third stage: Macrophages recruited to the site of injury by chemotactic factors are responsible for release of cytokines, angiogenic factors, and oxidants that perpetuate RPE injury and lead to late stages of AMD. Abbreviations: MPO = myeloperoxi‐ dase; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells; TNF-α: tumor necrosis factor-alpha; MCP-1: monocyte chemotactic protein-1; VEGF: vascular endothelial growth factor.
