Disruption of the cutaneous barrier by surgery or physical trauma exposes underlying tissue to the environment and can lead to infection. A robust inflammatory response serves to combat exogenous pathogens in injured tissue and is tightly coupled to the process of repair. Prolonged or excessive inflammation can impede tissue repair, suggesting that prompt resolution of inflammation governs this transition. The relationship between resolution of inflammation and tissue repair is incompletely understood. Resolvins are a family of lipid mediators generated by immune cells that promote resolution of inflammation and also enhance host defense. Our recent evidence indicates that resolvins and related pro-resolving mediators also play an important role in tissue repair. Project 3 of this Program Project will test the hypothesis that D-series resolvins and their newly- identified sulfido-conjugates (SC) promote cutaneous tissue repair and combat infection following surgical excisional injury. To test this hypothesis, the following specific aims will be carried out: 1) Assess the role of resolvins in cutaneous re-epithelialization. We will determine whether resolvins promote re-epithelialization and determine its relationship to the resolution of inflammation with Projects 1 & 2; 2) Elucidate the temporal biosynthetic relationships and endogenous roles of D-series resolvins during the inflammatory, proliferative and remodeling phases of the injury-repair response. Through interactions with Cores B & C and Projects 1 & 2, we will determine how biosynthesis of D-series resolvins and their SC are regulated during resolution and tissue repair. We will determine how pro-resolving receptors for RvD1 and RvD2 impact re-epithelialization in cutaneous surgical injury; 3) Establish the mechanisms whereby resolvins promote re-epithelialization. Using primary keratinocytes cultured in 2D and 3D, we will determine how resolvins regulate differentiation, migration and proliferation in a receptor-dependent manner; and 4) Determine whether resolvins restore defective re- epithelialization by combating bacterial infection. Here, we will examine how infection with skin pathogen, Staphylococcus aureus, impacts local resolvin biosynthesis and whether resolvins promote bacterial containment and re-establish epidermal barrier function. Collectively, Project 3 will provide fundamental new knowledge about the roles of resolvins in tissue repair, which can lead to the development of new therapeutic approaches for enhancing tissue repair and host defense.
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