Amelioration of Uveitis by Aldose reductase Inhibition

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Uveitis, an ocular inflammatory disease of unknown etiology, is a major complication during autoimmune disorders and infections and is associated with severe visual impairment. Uveitis may result from direct involvement of the uveal tract or indirect inflammation of adjacent eye tissues. Inflammation is an example of cytotoxicity caused by the formation of reactive oxygen species (ROS)-sensitive NF-KB dependent inflammatory cytokines and chemokines, and their autocrine and paracrine effects. However, the mechanisms through which increased ROS and inflammatory markers cause ocular inflammation are not well understood. Our recent studies have shown that aldose reductase (AR), which catalyzes the reduction of lipid peroxidation-generated lipid derived aldehydes (LDAs) and their glutathione conjugates, is an obligatory mediator of cytokine, chemokine, growth factor -induced activation of NF-KB and AP1 via PLC/PKC/IKKIMAPK in various cell lines including human lens epithelial cells (HLECs) and macrophages. We have also shown that AR inhibition prevents bacterial endotoxin (LPS)-induced production of inflammatory markers such as nitric oxide, TNF-a, PGE2 and Cox-2 in HLECs as well as in rat eyes. Our preliminary studies also suggest that AR inhibition prevents endotoxin and autoimmune-induced uveitis in rats. Therefore, our long-term goal is to understand the mechanisms by which AR contributes to ocular inflammation, and to use AR inhibitors to prevent uveitis and its associated complications in non-diabetics and diabetes. We will now systematically test our central hypothesis "that AR's catalytical activity plays a pivotal role in the transduction of ROS -induced inflammatory response leading to uveitis" by investigating the role of AR in mediating LPS-induced inflammatory response in cultured ocular epithelial cells as well as rodent models of uveitis.