The proposed experiments in Project 2 will test the hypothesis that in health, mucosal epithelial injury by noxious stimuli initiates airway formation of specialized pro-resolving mediators that promote resolution of acute inflammation and restitution of airway homeostasis. Published reports and preliminary data from ongoing collaborations with Projects 1, 3 and 4 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. Polyunsaturated fatty acids, including docosahexaenoic acid (C22:6), are present during airway inflammation and converted to bioactive lipid mediators. Some ofthese mediators, namely protectins, D-series resolvins, and maresins display anti-inflammatory and pro-resolving actions, including regulation of leukocyte trafficking to protect against neutrophil-mediated tissue injury, increased microbial clearance and enhanced mucosal epithelial host defense. Generation ofthe C22:6-derived protectins, D-series resolvins and maresins in airway injury and their capacity to block inflammation and promote resolution in the airway has not been evaluated. In addition to generation ofthese specialized pro-resolving mediators, their roles for organ protection at mucosal surfaces will be the focus of Project 2. To test our hypothesis, we propose three specific aims: * Determine the time course for specialized pro-resolving mediator formation after airway injury ? Actions of specialized pro-resolving mediators on airway epithelial functional responses, and * Establish the regulation of acute lung injury resolution by specialized pro-resolving mediators Project 2's specific aims on airway resolution pharmacology will be greatly facilitated by the synergy and unique resources to be provided by the proposed research program Projects and Cores and will enable us to (i) uncover new molecular insights into lipid-derived signaling pathways engaged during mucosal injury to the lower respiratory tract;and (ii) design novel therapeutic strategies that lessen the severity and consequent morbidity of acute lung injury and critical illnesses. .

Public Health Relevance

Tissue injury from noxious agents is common at mucosal surfaces, such as accidental aspiration of gastric acid, and can result in significant morbidity and critical illness, including the acute respiratory distress syndrome that has a mortality rate of over 25%. No specific medical therapies are available to promote resolution of mucosal tissue injury. New insights are needed to provide new therapeutic approaches

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZGM1-PPBC-3)
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Brigham and Women's Hospital
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