Resolution Mechanisms in Acute Inflammation: Resolution Pharmacology

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 DESCRIPTION (provided by applicant): When uncontrolled, infectious inflammation compromises organ function and is associated with many widely occurring human diseases of major public health concern. Surgery, trauma, and tissue injury can enable invading organisms to cause infections and inflammation that, if unresolved, can be fatal. These barrier breaks and microbial invasion evoke acute inflammation that is ideally protective and self-resolving. Resolution of inflammation was believed to occur via passive dilution of chemical mediators and pro-inflammatory molecules. From this Program Project, evidence emerged indicating resolution is an active molecular process orchestrated by new families of specialized pro-resolving mediators (SPM). These structurally distinct families include resolvins (Rv), protectins (PD), maresins (MaR) and their newly discovered potent SPM-sulfido-conjugates (SC) that resolve inflammation and stimulate tissue regeneration (Conjugates in Tissue Regeneration; CTR). Our overall mission in this renewal is to systematically elucidate the structures and functions of nove mediators in resolution and tissue regeneration. Our strategic plan includes lipid mediator (LM)-SPM-metabolipidomics with resolution and regeneration indices to interrogate inflammatory exudates and tissues coupled with total organic synthesis of SPM and SPM-SC standards to validate structure-function. The overarching novel hypothesis to be addressed by each project of this renewal requires a highly multi-disciplinary team and approach. Together, we shall test the following: Infectious inflammatory exudates evoked by tissue injury, surgical trauma and infection emit potent soluble chemical mediators locally such as SPM and their newly identified sulfido- conjugates that actively orchestrate resolution of inflammation, enhance microbial killing and clearance, as well as tissue regeneration. These new molecular resolution programs are essential for host defense and dictate severity and recovery intervals. This program project team is configured to address these unmet challenges and consists of 3 highly interactive projects, 2 scientific cores and an administrative core with expert advisory panels focused on establishing lipid mediator-resolution functional metabolome, stereo-controlled synthesis of SPM, SPM-SC and their specific mechanisms in resolution of infectious inflammation and clearance pathways. Our broad goal is to harness these molecules and pathways to bring forth resolution pharmacology for new treatments to control infectious inflammation and related tissue damage.