Local acute inflammation is protective and ideally should be self-limited. Our recent evidence indicates that resolution of sterile acute inflammation is an active process with the identification of novel specialized proresolving lipid-derived mediators (SPM) we coined resolvins and protectins. These local mediators possess potent anti-inflammatory and pro-resolving actions. It is now evident that the resolution of inflammation caused by apoptotic cells or bacterial invasion in model in vivo systems remains largely uncharted and is critically needed. The focus of Project 1 in this program project is the systematic elucidation of resolution components during self-limited verses un-resolved inflammation using an unbiased mediator-lipidomics approach with exudates. Using this approach, we recently uncovered a new family of lipid mediators coined maresins (macrophage mediators in resolving inflammation;MaR) that actively regulate both neutrophils (PMN) and macrophages. Project 1 will test the following novel hypothesis : During self-limited inflammation local production of novel anti-inflammatory and pro-resolving mediators in exudates enhances the clearance of apoptotic cells and microbes for timely resolution. Resolvins, protectins and maresins are a newly identified genus of SPM that temporally govern PMN and macrophage responses required for tissue resolution and return to homeostasis. To address this, 3 specific aims are proposed: 1) Determine temporal relationship between resolvin and protectin (SPM) biosynthesis during resolution. We will determine the key events involved in self-limited resolution with SPM and with Projects 2 and 3;2) Activation of novel maresins and resolvins during resolution. MaR display potent anti-inflammatory and proresolving actions.
This aim will focus on MaR biosynthesis and stereochemistry with Projects 4 and will establish pro-resolving and protective actions in models of human disease with Core C and 3) Impact of maresins and resolvins in phagocyte responses in resolution. Here, we will identify SPM that accelerate resolution, clearance phagocyte anti-microbial activities in mice and human phagocytes. Together results from these will establish the role of novel SPM in resolution of inflammation.

Public Health Relevance

Unresolved inflammation is now linked to many diseases (including sepsis, kidney and inflammatory bowel disease) increasing cause of death. In this program, Project 1 focuses on newly uncovered pathways and mediators which are the body's own anti-inflammatory and pro-resolving agents. Knowledge ofthese new pathways can open resolution pharmacology and permit better treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM095467-04
Application #
8641130
Study Section
Special Emphasis Panel (ZGM1-PPBC-3)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$391,797
Indirect Cost
$167,447
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Dalli, Jesmond; Colas, Romain A; Quintana, Carolina et al. (2017) Human Sepsis Eicosanoid and Proresolving Lipid Mediator Temporal Profiles: Correlations With Survival and Clinical Outcomes. Crit Care Med 45:58-68
Serhan, Charles N; Chiang, Nan; Dalli, Jesmond (2017) New pro-resolving n-3 mediators bridge resolution of infectious inflammation to tissue regeneration. Mol Aspects Med :
English, Justin T; Norris, Paul C; Hodges, Robin R et al. (2017) Identification and Profiling of Specialized Pro-Resolving Mediators in Human Tears by Lipid Mediator Metabolomics. Prostaglandins Leukot Essent Fatty Acids 117:17-27
Norris, Paul C; Libreros, Stephania; Chiang, Nan et al. (2017) A cluster of immunoresolvents links coagulation to innate host defense in human blood. Sci Signal 10:
Bowden, John A; Heckert, Alan; Ulmer, Candice Z et al. (2017) Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-Metabolites in Frozen Human Plasma. J Lipid Res 58:2275-2288
Flitter, Becca A; Hvorecny, Kelli L; Ono, Emiko et al. (2017) Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators. Proc Natl Acad Sci U S A 114:136-141
Chiang, Nan; Serhan, Charles N (2017) Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors. Mol Aspects Med 58:114-129
Fredman, Gabrielle; Spite, Matthew (2017) Specialized pro-resolving mediators in cardiovascular diseases. Mol Aspects Med 58:65-71
Hansen, Trond Vidar; Dalli, Jesmond; Serhan, Charles N (2017) The novel lipid mediator PD1n-3 DPA: An overview of the structural elucidation, synthesis, biosynthesis and bioactions. Prostaglandins Other Lipid Mediat 133:103-110
Laan, Lisa C; Williams, Andrew R; Stavenhagen, Kathrin et al. (2017) The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells. FASEB J 31:719-731

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