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 #
5P01GM095467-10
Application #
9906237
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Serhan, Charles N; Chiang, Nan; Dalli, Jesmond (2018) New pro-resolving n-3 mediators bridge resolution of infectious inflammation to tissue regeneration. Mol Aspects Med 64:1-17
Dalli, Jesmond; Colas, Romain A; Walker, Mary E et al. (2018) Lipid Mediator Metabolomics Via LC-MS/MS Profiling and Analysis. Methods Mol Biol 1730:59-72
Lahvic, Jamie L; Ammerman, Michelle; Li, Pulin et al. (2018) Specific oxylipins enhance vertebrate hematopoiesis via the receptor GPR132. Proc Natl Acad Sci U S A 115:9252-9257
Serhan, Charles N; Levy, Bruce D (2018) Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest 128:2657-2669
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:
de la Rosa, Xavier; Norris, Paul C; Chiang, Nan et al. (2018) Identification and Complete Stereochemical Assignments of the New Resolvin Conjugates in Tissue Regeneration in Human Tissues that Stimulate Proresolving Phagocyte Functions and Tissue Regeneration. Am J Pathol 188:950-966
Hellmann, Jason; Sansbury, Brian E; Wong, Blenda et al. (2018) Biosynthesis of D-Series Resolvins in Skin Provides Insights into their Role in Tissue Repair. J Invest Dermatol 138:2051-2060
Hvorecny, Kelli L; Dolben, Emily; Moreau-Marquis, Sophie et al. (2018) An epoxide hydrolase secreted by Pseudomonas aeruginosa decreases mucociliary transport and hinders bacterial clearance from the lung. Am J Physiol Lung Cell Mol Physiol 314:L150-L156

Showing the most recent 10 out of 165 publications