Amelioration of Uveitis by Aldose reductase Inhibition

通过抑制醛糖还原酶来改善葡萄膜炎

• 批准号: 7650980
• 负责人: KOTA VENKATA RAMANA
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650980
• 关键词: Ablation; Accounting; Adverse effects; Aldehyde Reductase; Aldehydes; Animal Model; Anti-Inflammatory Agents; Antioxidants; Aqueous Humor; Attenuated; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacterial Infections; Blindness; Blood Vessels; CCL2 gene; Cattle; Cell Line; Cell physiology; Cells; Chronic; Clinic; Complication; Data; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Diabetic Neuropathies; Dinoprostone; Disease; Dose; E-Selectin; Endocrinology; Endotoxins; Enzymes; Epithelial Cells; Etiology; Extravasation; Eye; Foundations; Functional disorder; Future; Glutathione; Goals; Growth Factor; Health Services Accessibility; Homeostasis; Human; Hyperglycemia; Immune response; Immune system; In Vitro; Incidence; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Intercellular adhesion molecule 1; Interleukin-1; Interleukin-17; Interleukin-6; Investigation; Knockout Mice; Leukocytes; Leukostasis; Light; Lipid Peroxidation; Lipids; Lipopolysaccharides; Lymphocyte; Macrophage Inflammatory Protein-1; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolism; Methods; Modeling; Molecular; Molecular Target; Monitor; Mus; Nitric Oxide; Normal tissue morphology; Oxidation-Reduction; Oxidative Stress; Participant; Pathology; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phase III Clinical Trials; Play; Positioning Attribute; Production; Property; Proteins; Publishing; Quality of life; Rattus; Reactive Oxygen Species; Regulation; Reporting; Retinal; Risk; Rodent Model; Role; Serum; Severities; Signal Pathway; Signal Transduction; Steroids; Subcutaneous Injections; Symptoms; Testing; Therapeutic; Tissues; Transcription Factor AP-1; Uvea; Uveitis; Vision; Visual impairment; Vitreous Chamber; activating transcription factor; adduct; autocrine; base; chemokine; cytokine; cytotoxic; cytotoxicity; diabetic; experience; fidarestat; in vivo; inflammatory marker; inhibitor/antagonist; innovation; interstitial retinol-binding protein; lens; macrophage; mouse model; non-diabetic; novel; novel therapeutic intervention; paracrine; prevent; transcription factor

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.

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的直接受累或邻近眼组织的间接炎症引起。炎症是由活性氧（ROS）敏感性NF-κ B依赖性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实例。然而，增加的ROS和炎症标记物引起眼部炎症的机制并不清楚。 很好理解。我们最近的研究已经表明，催化脂质过氧化产生的脂质衍生的醛（LDA）及其谷胱甘肽缀合物的还原的醛糖还原酶（AR）是细胞因子、趋化因子、生长因子诱导的NF-κ B和AP 1在包括人透镜上皮细胞（HLEC）和巨噬细胞在内的各种细胞系中经由PLC/PKC/IKKIMAPK活化的强制性介体。 我们还表明，AR抑制防止细菌内毒素（LPS）诱导的HLEC以及大鼠眼中炎性标志物如一氧化氮、TNF-α、PGE 2和考克斯-2的产生。我们的初步研究还表明，AR抑制防止内毒素和自身免疫诱导的葡萄膜炎大鼠。因此，我们的长期目标是了解AR导致眼部炎症的机制，并使用AR抑制剂预防非糖尿病患者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，即AR的催化活性起着重要作用。 通过研究AR在培养的眼上皮细胞以及葡萄膜炎的啮齿动物模型中介导LPS诱导的炎症反应中的作用，