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. ? ? ? ?
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