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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
2P01GM095467-06
Application #
9068636
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
Motwani, Madhur P; Colas, Romain A; George, Marc J et al. (2018) Pro-resolving mediators promote resolution in a human skin model of UV-killed Escherichia coli-driven acute inflammation. JCI Insight 3:
Gromovsky, Anthony D; Schugar, Rebecca C; Brown, Amanda L et al. (2018) ?-5 Fatty Acid Desaturase FADS1 Impacts Metabolic Disease by Balancing Proinflammatory and Proresolving Lipid Mediators. Arterioscler Thromb Vasc Biol 38:218-231
Halade, Ganesh V; Norris, Paul C; Kain, Vasundhara et al. (2018) Splenic leukocytes define the resolution of inflammation in heart failure. Sci Signal 11:
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Winkler, Jeremy W; Libreros, Stephania; De La Rosa, Xavier et al. (2018) Structural insights into Resolvin D4 actions and further metabolites via a new total organic synthesis and validation. J Leukoc Biol :
Wu, Bian; Werlin, Evan C; Chen, Mian et al. (2018) Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model. J Vasc Surg 68:188S-200S.e4
Motwani, Madhur P; Bennett, Frances; Norris, Paul C et al. (2018) Potent Anti-Inflammatory and Pro-Resolving Effects of Anabasum in a Human Model of Self-Resolving Acute Inflammation. Clin Pharmacol Ther 104:675-686
Norris, Paul C; Arnardottir, Hildur; Sanger, Julia M et al. (2018) Resolvin D3 multi-level proresolving actions are host protective during infection. Prostaglandins Leukot Essent Fatty Acids 138:81-89

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