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.
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.
|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|
|Chiang, Nan; Riley, Ian R; Dalli, Jesmond et al. (2018) New maresin conjugates in tissue regeneration pathway counters leukotriene D4-stimulated vascular responses. FASEB J 32:4043-4052|
|Krishnamoorthy, Nandini; Abdulnour, Raja-Elie E; Walker, Katherine H et al. (2018) Specialized Proresolving Mediators in Innate and Adaptive Immune Responses in Airway Diseases. Physiol Rev 98:1335-1370|
|Chen, Gang; Zhang, Yu-Qiu; Qadri, Yawar J et al. (2018) Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain. Neuron 100:1292-1311|
|Tungen, J E; Aursnes, M; Ramon, S et al. (2018) Synthesis of protectin D1 analogs: novel pro-resolution and radiotracer agents. Org Biomol Chem 16:6818-6823|
|Sulciner, Megan L; Serhan, Charles N; Gilligan, Molly M et al. (2018) Resolvins suppress tumor growth and enhance cancer therapy. J Exp Med 215:115-140|
|Loynes, Catherine A; Lee, Jou A; Robertson, Anne L et al. (2018) PGE2 production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolution in vivo. Sci Adv 4:eaar8320|
|Zhang, Linlin; Terrando, Niccolò; Xu, Zhen-Zhong et al. (2018) Distinct Analgesic Actions of DHA and DHA-Derived Specialized Pro-Resolving Mediators on Post-operative Pain After Bone Fracture in Mice. Front Pharmacol 9:412|
|Dalli, Jesmond; Serhan, Charles N (2018) Immunoresolvents signaling molecules at intersection between the brain and immune system. Curr Opin Immunol 50:48-54|
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