Disease Basis 61231 Glaucoma

Elevation of IOP results from a deposition of extracellular matrix (ECM) in the anterior chamber, and thus blockage of the AH drainage pathway, the TM and Schlemm's canal. The ECM is composed of numerous proteins, modified glycoproteins, and glycosaminoglycans, including hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratin sulfate, and heparin sulfate. The abnormal deposition and/or clearance of ECM in glaucomatous patients may also result from TM cell death and loss of phagocytic activity during the aging process. Coupled with these phenomena is perhaps the decreased ability of TM cells to liberate local matrix metalloproteinases (MMPs), that can digest the ECM and remodel and maintain the anterior chamber architecture and function. There is increasing evidence that increased concentration of tissue growth factor-^2 (TGF-P2) observed in ocular hypertensive glaucoma patients contributes to the elevation of ECM in the TM. The loss of MMP activity could also be due to TGF-^2.10 In addition, a soluble glycoprotein (sCD44) derived from the hyaluronic acid receptor (CD44H) found in the AH of glaucoma patients appears to be toxic to TM cells,11 and may be responsible for the decreased TM cellularity in glaucoma patients' eyes. Perhaps deposition of other neurotoxic apolipoproteins, including serum amyloid-A (SAA)12 and/or amyloid-b and related proteins13 in the anterior chamber of the eye and/or in the retina, could also be involved in the etiology of ocular hypertension and glaucoma. A recent study strongly correlated RGC apoptosis with elevated IOP and ECM deposition,14 thus strengthening the link between ocular hypertension and loss. Consequently, the mainstay pharmaceutical treatment for POAG has been to treat ocular hypertension either by limiting the generation of AH by the ciliary body or by promoting the efflux of the AH from the anterior chamber. Since the AH can leave the eye via the TM/Schlemm's canal (conventional outflow) and via the spaces between the ciliary muscle bundles and into venous blood vessels (uveoscleral outflow), therapeutic approaches have focused recently on reducing IOP by the latter pathways rather than reducing AH production. Agents that reduce AH production can actually deprive the anterior chamber tissues of much needed nutrients and oxygen, and reduce the elimination of waste products. However, patients refractory to outflow agents have to rely on drugs that reduce inflow and/or undergo surgical treatments such as laser trabeculoplasty and/or filtration surgery (see below).

When considering potential causes and treatments of macular degeneration, it is informative to consider the normal vision process from a functional and morphological standpoint. Light that is transmitted through the surface and the anterior chamber of the eye is absorbed in the outer retina by opsin-bound (as a Schiff base) retinaldehyde, which is present in specialized light-gathering cells called photoreceptors. There are two types of photoreceptors: rods, which are used primarily for low light vision, and cones, which are responsible for color perception and visual acuity. Light-induced isomerization of the retinaldehyde Schiff base position 11 olefin from cis to trans geometry generates a signal, which is converted to a nerve impulse for eventual relay to RGCs in the inner retina (Figure 2). RGCs transmit this signal through the optic nerve head (ONH) and into the brain, where the signal is integrated.

Photoreceptor function is only possible with the support of specialized cells in the retinal pigmented epithelium (RPE). These RPE cells take up released 11-trans-retinaldehyde (in the form of the reduced retinol) and isomerize the olefin geometry back to the photoactive 11-cis form. RPE cells also phagocytize photoreceptor outer membrane segments that are continuously shed and replaced. Choroidal capillaries provide nutritional support (oxygen, proteins, hormones, etc.) to and remove waste products from photoreceptors and RPE cells, and are separated from them by

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