Amelioration of Uveitis by Aldose reductase Inhibition

葡萄膜炎是一种病因不明的眼部炎症性疾病，是自身免疫性疾病和感染的主要并发症，并与严重的视力损害有关。葡萄膜炎可由葡萄膜束直接受累或相邻眼组织间接发炎引起。炎症是由活性氧（ROS）敏感的NF-KB依赖性炎症细胞因子和趋化因子的形成及其自分泌和旁分泌作用引起的细胞毒性的一个例子。然而，ROS和炎症标志物增加引起眼部炎症的机制尚不清楚

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.