Proliferative vitreoretinopathy (PVR), the leading cause of rhegmatogenous retinal detachment (RRD) surgical failure, is a potentially blinding disease. The long-term project goal is to understand how cytokines trigger and perpetuate PVR. This information will lead to more effective treatment strategies designed to prevent or inhibit this condition, and will help to explain why some patients develop progressive disease while others do not. Based on data from the current funding period, the following hypotheses have been developed: The transcription factor NF-kappaB is a key regulator of cytokine expression in retinal pigment epithelial (RPE) cells, and inhibits RPE apoptosis. Cytokine-mediated, cell density-dependent activation of NF-kappaB in RPE cells promotes and perpetuates PVR. Contemporary cell and molecular biological techniques will be employed to address the following Specific Aims: I) To determine whether RPE cell density regulates interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFalpha)-mediated NF-kappaB activation. The effect of cell density on IL-1 and TNF receptor number and receptor-activated NF-kappaB activity will be quantified in cultured human RPE cells. II) To determine whether specific factors relevant to PVR or its treatment downregulate cytokine-activated NF-kappaB in RPE cells. The effect of transforming growth factor beta2 (TGF-beta2) and subretinal fluid from patients with RRD, on RPE cell NF-kappaB activation will be determined. III) To determine whether NF-kappaB regulates RPE cell apoptosis. Density-dependent effects of IL-1, TNFalpha, and specific NF-kappaB inhibitors on NF-kappaB-mediated RPE apoptosis will be quantified. IV) To determine whether specific in vivo NF-kappaB blockade inhibits PVR.
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