In many human conditions (e.g. inflammatory bowel disease, sepsis, multi-organ injury and failure), the progression from acute inflammatory insult to either resolution or chronicity remains impossible to predict. Our recent findings indicate that resolution of local inflammation involves active resolution circuits that generate a novel genus of potent Specialized Pro-Resolving Mediators (SPM). SPM are comprised of distinct structural families of lipid mediators (LM) including resolvins, protectins and maresins derived from essential omega-3 fatty acids. Novel SPM that are potent anti-inflammatories also stimulate uptake of apoptotic neutrophils, microbial containment and their clearance by phagocytes and mucosal epithelia. These findings reveal an urgent clinical need to navigate resolution to establish fundamental mechanisms in resolution pharmacology. To address this health mission, a multidisciplinary team of experts is assembled in this program project that will use a systematic approach to elucidate cellular and molecular mechanisms in self-limited experimental systems. Our team and overall project is focused on elucidating programmed resolution of acute inflammation with an emphasis on LM, SPM and resolution pharmacology for new treatments. Ongoing studies give rise to an overarching hypothesis tested by four highly complementary integrated projects with synergistic approaches. The overall novel hypothesis addressed is: Resolvins, protectins and maresins constitute a new genus of SPM that temporally regulate endogenous anti inflammatory and pro-resolving pathways. SPM govern resolution via regulated leukocyte responses, enhanced mucosal defense and bacterial containment these molecular events can be harnessed for novel resolution pharmacology to treat diseases. This P01 team consists of 4 projects, 2 scientific cores and an advisory unit focused on establishing LM-resolution metabolome, stereo-controlled synthesis of SPM and their specific mechanisms in resolution, anti-inflammatory and clearance pathways. Selected synthetic SPM will be scaled-up for demonstration of their unique mode of action in vivo in a resolution pharmacology core using experimental disease models. Our broad goal is to bring forth new treatments in resolution.

Public Health Relevance

To improve patient care, a goal of this program project is to harness new specialized pro-resolving mediators (SPM) and resolution pharmacology as a new therapeutic approach to better treat human diseases and tissue injury where resolving local inflammation is important. The potential for resolution pharmacology in new treatments could diminish the healthcare burden of inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM095467-02
Application #
8245841
Study Section
Special Emphasis Panel (ZGM1-PPBC-3 (CP))
Program Officer
Okita, Richard T
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$1,361,099
Indirect Cost
$457,065
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Awji, Elias G; Chand, Hitendra; Bruse, Shannon et al. (2015) Wood smoke enhances cigarette smoke-induced inflammation by inducing the aryl hydrocarbon receptor repressor in airway epithelial cells. Am J Respir Cell Mol Biol 52:377-86
Krishnamoorthy, Nandini; Burkett, Patrick R; Dalli, Jesmond et al. (2015) Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation. J Immunol 194:863-7
Wang, Xiuzhe; Zhu, Mingqin; Hjorth, Erik et al. (2015) Resolution of inflammation is altered in Alzheimer's disease. Alzheimers Dement 11:40-50.e1-2
Serhan, Charles N; Dalli, Jesmond; Colas, Romain A et al. (2015) Protectins and maresins: New pro-resolving families of mediators in acute inflammation and resolution bioactive metabolome. Biochim Biophys Acta 1851:397-413
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Spite, Matthew; Claria, Joan; Serhan, Charles N (2014) Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases. Cell Metab 19:21-36
Abdulnour, Raja-Elie E; Dalli, Jesmond; Colby, Jennifer K et al. (2014) Maresin 1 biosynthesis during platelet-neutrophil interactions is organ-protective. Proc Natl Acad Sci U S A 111:16526-31
Colas, Romain A; Shinohara, Masakazu; Dalli, Jesmond et al. (2014) Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. Am J Physiol Cell Physiol 307:C39-54
Tang, Huifang; Liu, Yanlan; Yan, Chunguang et al. (2014) Protective actions of aspirin-triggered (17R) resolvin D1 and its analogue, 17R-hydroxy-19-para-fluorophenoxy-resolvin D1 methyl ester, in C5a-dependent IgG immune complex-induced inflammation and lung injury. J Immunol 193:3769-78

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