"Corneal Arachidonate Metabolites via Cytochrome P450"

“通过细胞色素 P450 进行角膜花生四烯酸代谢”

• 批准号: 7676002
• 负责人: Michal Laniado Schwartzman
• 金额: $ 38.6万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676002
• 关键词: Acids; Adhesions; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Attenuated; Bilirubin; Biliverdine; Biochemical Reaction; Biochemistry; Blindness; CCL2 gene; CYP4B1 gene; Carbon Monoxide; Cell physiology; Cells; Cornea; Corneal Injury; Corneal Neovascularization; Cytochrome P450; Data; Eicosanoids; Equilibrium; Event; Functional disorder; Healed; Heme; Human; Hypoxia; IL8 gene; Immune; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Lead; Leukocytes; Light; Lipids; Mediating; Mediator of activation protein; Modeling; Mus; Operative Surgical Procedures; Oryctolagus cuniculus; Oxidative Stress; Oxygenases; Pathway interactions; Perforation; Play; Process; Production; Proteins; Regulation; Reporting; Research Personnel; Resolution; Role; Seminal; Signal Transduction; Signaling Molecule; Structure; Supplementation; Surgical sutures; System; Testing; Tissues; Ulcer; Vascular Endothelial Growth Factors; Work; Wound Healing; arachidonate; base; chemokine; corneal epithelium; cytokine; genetic manipulation; healing; heme oxygenase-1; heme oxygenase-2; in vivo; migration; neovascularization; neutrophil; new therapeutic target; novel; ocular surface; overexpression; programs; repaired; response; response to injury; restoration; wound

DESCRIPTION: This is a proposal to investigate the role of the heme oxygenase (HO) system in the regulation of the corneal inflammatory and reparative response to injury. This vital inflammatory response is marked by activation of corneal cells and recruitment of leukocytes to produce lipid and protein mediators that initiate and amplify inflammation. Aberrant activation of these pathways can lead to tissue destruction and loss of vision. To maintain the cornea as an optically transparent barrier, a self-resolving inflammatory-reparative process is needed to balance inflammation and immune privilege while promoting wound repair. This process must include pro- and anti-inflammatory circuits that work in concert to initiate, mediate and resolve inflammation allowing the repair process to proceed. The HO system (HO-1 and HO-2) has emerged as a fundamental endogenous cytoprotective and anti-inflammatory system. It is readily upregulated in response to injury and its activity results in less tissue damage with reduction of inflammatory events such as leukocyte adhesion/migration and production of inflammatory cytokines, yet little is known about the role of the HO system in the cornea. Studies demonstrating that HO induction reduced inflammation and neovascularization in the hypoxic cornea, an effect associated with reduced expression of a key pro- inflammatory circuit, the CYP4B1-derived 12-HETrE, and that HO deficiency causes an aberrant inflammatory and reparative response with a sustained increase in inflammatory cells, impaired wound closure, ulceration, perforation and neovascularization with increased CYP4B1-12-HETRrE levels led to our hypothesis: The HO system (HO-1 and HO-2) is an endogenous anti-inflammatory and protective circuit critical for a self-resolving inflammatory-reparative process in the cornea; it acts through its catalytic products, biliverdin/bilirubin and CO, to modulate leukocyte migration and inhibit key proinflammatory circuits (CYP4B1-12-HETrE), thereby, promoting resolution and repair. With pharmacological and genetic manipulations of the HO system in two models of corneal injury, we will examine its role in injury response and the mechanisms underlying HO cytoprotective and anti-inflammatory functions. These studies have the potential to uncover a critical endogenous anti-inflammatory circuitin the cornea and a new target for therapeutic strategies to treat inflammation associated with corneal injury, infection, ulceration and surgery.

描述：本提案旨在研究血红素加氧酶 (HO) 系统在调节角膜炎症和损伤修复反应中的作用。这种重要的炎症反应的特点是角膜细胞的激活和白细胞的募集，以产生引发和放大炎症的脂质和蛋白质介质。这些通路的异常激活可能导致组织破坏和视力丧失。为了保持角膜作为光学透明屏障，需要一种自我解决的炎症修复过程来平衡炎症和免疫特权，同时促进伤口修复。这个过程必须包括促炎和抗炎回路，它们协同工作以启动、介导和解决炎症，从而使修复过程继续进行。 HO 系统（HO-1 和 HO-2）已成为基本的内源性细胞保护和抗炎系统。它在损伤反应中很容易上调，其活性可减少组织损伤，减少炎症事件，如白细胞粘附/迁移和炎症细胞因子的产生，但人们对 HO 系统在角膜中的作用知之甚少。研究表明，H2O 诱导减少了缺氧角膜中的炎症和新生血管形成，这种作用与关键促炎回路（CYP4B1 衍生的 12-HETrE）表达减少有关，并且 H2O 缺乏会导致异常的炎症和修复反应，并持续随着 CYP4B1-12-HETRrE 水平增加，炎症细胞增加、伤口闭合受损、溃疡、穿孔和新生血管形成，导致我们的假设：HO 系统（HO-1 和 HO-2）是一种内源性抗炎和保护回路，对于角膜的自消炎修复过程至关重要；它通过其催化产物胆绿素/胆红素和 CO 发挥作用，调节白细胞迁移并抑制关键的促炎回路 (CYP4B1-12-HETrE)，从而促进消退和修复。通过在两种角膜损伤模型中对 HO 系统进行药理学和遗传操作，我们将研究其在损伤反应中的作用以及 HO 细胞保护和抗炎功能的机制。这些研究有可能揭示角膜中关键的内源性抗炎回路，并为治疗与角膜损伤、感染、溃疡和手术相关的炎症的治疗策略提供新的靶点。