Amelioration of Uveitis by Aldose reductase Inhibition

葡萄膜炎是一种原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管直接受累或邻近眼组织间接发炎引起。炎症是由反应性氧物种(ROS)敏感的依赖于NF-KB的炎性细胞因子和趋化因子的形成及其自分泌和旁分泌效应引起的细胞毒性的一个例子。然而，ROS和炎症标志物增加导致眼部炎症的机制尚不清楚 很好理解。我们最近的研究表明，在包括人晶状体上皮细胞(HLECs)和巨噬细胞在内的多种细胞系中，醛糖还原酶(AR)是细胞因子、趋化因子、生长因子通过PLC/PKC/IKKIMAPK诱导的NF-KB和AP1活化的必备介质，它催化脂质过氧化生成的脂质衍生醛(LDAs)及其谷胱甘肽结合物。 我们还表明，AR抑制可阻止细菌内毒素(LPS)诱导的炎症标记物，如HLEC和大鼠眼睛中一氧化氮、肿瘤坏死因子-α、前列腺素E_2和环氧合酶-2的产生。我们的初步研究还表明，AR抑制可以预防内毒素和自身免疫性葡萄膜炎。因此，我们的长期目标是了解AR促进眼部炎症的机制，并使用AR抑制剂来预防非糖尿病和糖尿病患者的葡萄膜炎及其相关并发症。 我们现在将系统地测试我们的中心假设：AR的催化活性对 在ROS诱导的炎症反应导致葡萄膜炎的转导中的关键作用“，通过在培养的眼上皮细胞和啮齿动物葡萄膜炎模型中研究AR在介导LPS诱导的炎症反应中的作用。

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.