In this renewal application, Project 2 will test the hypothesis that specialized pro-resolving mediators (SPM) and their sulfido-conjugates (SPM-SCs) are locally produced in mucosal tissues in response to injury or infection to restore function by enhancing the resolution inflammation and clearance of infection. Published reports and preliminary data from ongoing collaborations with Projects 1, 3 and the Cores have identified pivotal roles for airway epithelia and leukocytes in regulating acute inflammation, injury and host defense. In the common clinical setting of aspiration, disruption of airway epithelial integrity by gastric acid leads to tissue injury and an increased susceptibility to infection that can result in the acute respiratory distress syndrome (ARDS). Polyunsaturated fatty acids, including docosahexaenoic acid (DHA), are present in mucosal tissues and cells during airway inflammation and converted to bioactive mediators that display anti-inflammatory and pro-resolving actions, including regulation of leukocyte trafficking. In the current funding cycle of this P01, we have uncovered temporal and spatial regulation of the production of DHA-derived maresin 1 in airway injury and its capacity to promote resolution of lung inflammation. The cell type specific actions of maresins and their related SPM-SCs as well as their role in host defense remains of interest. In addition to SPM and SPM-SC local production at sites of tissue inflammation, injury or infection, their roles for organ protection at mucosal surfaces will be the focus of Project 2. To test our hypothesis, we propose four specific aims: Determine the impact of Maresins and their SPM-SCs on the resolution of ARDS and pneumonia Determine pro-resolving actions for Maresins and SPM-SCs on airway epithelial and lung macrophage protective responses Determine relationships between SPM, SPM-SC and catabasis of tissue injury and infection, and Demonstration of local SPM function in resolution in vivo in human exudates Project 2's specific aims on airway resolution pharmacology will be greatly facilitated by the synergy and unique resources provided by the proposed renewal of the Program Projects and Cores that will enable us to (i) uncover new molecular insights into signaling pathways engaged during mucosal tissue injury; and (ii) design novel therapeutic strategies that lessen the severity and consequent morbidity of ARDS and pneumonia.
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