Proliferative vitreoretinopathy (PVR) is characterized by abnormal proliferation of cells on both surfaces of the retina and the vitreous face, deposition of collagen and other extracellular matrix materials, and eventual contraction of the membranes formed, resulting in traction retinal detachment. Proliferative vitreoretinopathy is the most common cause of failure in retinal reattachment surgery. The factors that stimulate cell growth are at present unknown although fibronectin and platelet derived growth factor have recently been implicated. The purposes of the proposed studies are to better understand the disease by determining the mechanisms that lead to the cellular proliferation and membrane contraction and to develop means of prevention. We hypothesize that alterations in arachidonic acid metabolism and breakdown of the blood ocular barriers following retinal detachment surgery or other trauma results in the accumulation of substances in the vitreous cavity that stimulate chemotaxis, attachment, contraction, and proliferation of cells on available or newly synthesized extracellular matrices. We propose to test this hypothesis by interfering with arachidonic acid metabolism, cell attachment, and cell contraction in order to determine if we can prevent cellular proliferation and contraction in vitro and in animal models for proliferative vitreoretinopathy. Arachidonic metabolism will be blocked by selective inhibitors of the cyclo-oxygenase and lipoxygenase pathways as well as by inhibitors of both pathways. The effect on cell proliferation will be determined in animal models of proliferative vitreoretinopathy. Time lapse photography and computerized image analysis will be used to evaluate tractional forces exerted on a silicone rubber substratum by cultured cells. Adhesion proteins will be removed and inhibitors of smooth muscle contraction will be applied in order to determine the effect on cell contraction and proliferation in vitro and in vivo. Finally, combinations of drugs will be evaluated for efficacy and similar experiments will be done using animal eyes (cat, primate) that have a response to injury that is more similar to human than is rabbit. The results of these studies will lead to a better understanding of the mechanisms involved in abnormal proliferation of cells in the eye and could lead to means of preventing or influencing the early course of PVR and other proliferative diseases of the eye.
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