"Corneal Arachidonate Metabolites via Cytochrome P450"

目的：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。这一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，以产生启动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。为了维持角膜作为光学透明屏障的作用，需要一个自我分解的炎症-修复过程，以平衡炎症和免疫豁免，同时促进伤口修复。这一过程必须包括协同工作的促炎和抗炎回路，以启动、调节和化解炎症，从而使修复过程继续进行。HO系统(HO-1和HO-2)是一种基本的内源性细胞保护和抗炎系统。它很容易在损伤时上调，其活性导致较少的组织损伤，减少炎症事件，如白细胞黏附/迁移和炎性细胞因子的产生，但对HO系统在角膜中的作用知之甚少。研究表明，HO诱导减少了缺氧性角膜的炎症和新生血管，这一效应与关键的促炎通路--由CYP4B1衍生的12-HETrE的表达减少有关，并且HO缺乏导致异常的炎症和修复反应，炎症细胞持续增加，伤口闭合受损，溃疡，穿孔和新生血管，并增加CYP4B1-12-HETRrE水平，导致我们的假说：HO系统(HO-1和HO-2)是内源性抗炎和保护回路，对角膜的自我消炎-修复过程至关重要；它通过其催化产物胆绿素/胆红素和一氧化碳，调节白细胞的迁移并抑制关键的致炎通路(CYP4B1-12-HETrE)，从而促进分解和修复。通过对HO系统在两种角膜损伤模型中的药理学和遗传学操作，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一个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提供新的靶点。

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.