"Corneal Arachidonate Metabolites via Cytochrome P450"

产品说明：本研究旨在探讨血红素氧合酶（HO）系统在角膜炎症和损伤修复反应中的作用。这种重要的炎症反应以角膜细胞的活化和白细胞的募集为标志，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，需要自我解决的炎症修复过程来平衡炎症和免疫豁免，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，从而使修复过程得以进行。HO系统（HO-1和HO-2）已经成为基本的内源性细胞保护和抗炎系统。HO系统对损伤的反应很容易上调，其活性导致较少的组织损伤，减少炎症事件，如白细胞粘附/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诱导减少了缺氧角膜中的炎症和新血管形成，这是一种与关键促炎回路CYP 4 B1衍生的12-HETrE的表达减少相关的效应，并且HO缺乏引起异常的炎症和修复反应，伴随炎症细胞的持续增加、受损的伤口闭合、溃疡，穿孔和新血管形成与CYP 4 B1 -12-HETRrE水平升高导致我们的假设：HO系统HO-1和HO-2是一种内源性抗炎和保护性回路，对于角膜中的自我解决炎症修复过程至关重要;它通过其催化产物胆绿素/胆红素和CO调节白细胞迁移并抑制关键的促炎回路（CYP 4 B1 -12-HETrE），从而促进消退和修复。通过两种角膜损伤模型中HO系统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关键的内源性抗炎循环，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。

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.