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

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM095467-02
Application #
8375337
Study Section
Special Emphasis Panel (ZGM1-PPBC-3)
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$384,646
Indirect Cost
$160,115
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Primdahl, Karoline G; Aursnes, Marius; Walker, Mary E et al. (2016) Synthesis of 13(R)-Hydroxy-7Z,10Z,13R,14E,16Z,19Z Docosapentaenoic Acid (13R-HDPA) and Its Biosynthetic Conversion to the 13-Series Resolvins. J Nat Prod 79:2693-2702
Duvall, Melody G; Levy, Bruce D (2016) DHA- and EPA-derived resolvins, protectins, and maresins in airway inflammation. Eur J Pharmacol 785:144-55
Ramon, Sesquile; Dalli, Jesmond; Sanger, Julia M et al. (2016) The Protectin PCTR1 Is Produced by Human M2 Macrophages and Enhances Resolution of Infectious Inflammation. Am J Pathol 186:962-73
Hansen, Trond V; Dalli, Jesmond; Serhan, Charles N (2016) Selective identification of specialized pro-resolving lipid mediators from their biosynthetic double di-oxygenation isomers. RSC Adv 6:28820-28829
Freire, Marcelo O; Dalli, Jesmond; Serhan, Charles N et al. (2016) Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes. J Immunol :
Sorokin, Alexander V; Yang, Zhi-Hong; Vaisman, Boris L et al. (2016) Addition of aspirin to a fish oil-rich diet decreases inflammation and atherosclerosis in ApoE-null mice. J Nutr Biochem 35:58-65
Winkler, Jeremy W; Orr, Sarah K; Dalli, Jesmond et al. (2016) Resolvin D4 stereoassignment and its novel actions in host protection and bacterial clearance. Sci Rep 6:18972
Zhu, Mingqin; Wang, Xiuzhe; Hjorth, Erik et al. (2016) Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Aβ42 Phagocytosis. Mol Neurobiol 53:2733-49
Mayurasakorn, Korapat; Niatsetskaya, Zoya V; Sosunov, Sergey A et al. (2016) DHA but Not EPA Emulsions Preserve Neurological and Mitochondrial Function after Brain Hypoxia-Ischemia in Neonatal Mice. PLoS One 11:e0160870
Dalli, Jesmond; Vlasakov, Iliyan; Riley, Ian R et al. (2016) Maresin conjugates in tissue regeneration biosynthesis enzymes in human macrophages. Proc Natl Acad Sci U S A 113:12232-12237

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