Tissue injury and microbial invasion evoke acute inflammation that is usually protective and ideally should be "self-limited". The resolution phase of acute inflammation was believed to be passive and defined earlier by histology of tissue processes leading from acute inflammation back to homeostasis. In this Project 4 leader's laboratory and now others worldwide, evidence has emerged indicating that resolution is an active process with the Identification and synthesis of a novel genus of specialized pro-resolving mediators (SPM). These local-acting, distinct families of molecules are non-redundant and include resolvins, lipoxins and protectins. These SPM are potent anti-inflammatory and pro-resolving signals. With new flndings from animal disease models including sepsis from cecal ligation and puncture, it has become evident that the resolution program of acute inflammation is largely uncharted and is needed to improve patient care. The focus of Project 4 within the Translational P01 is the systematic elucidation of low-dose inhaled carbon monoxide (CO) on activating resolution components using unbiased lipid mediator (LM)-lipidomics with resolution indices, an approach developed in the Serhan lab with inflammatory exudates. Because phagocytes, e.g. neutrophils and macrophages, are key in the release of pro-inflammatory lipid mediators including leukotrienes and prostaglandins that can affect organ function, this project will focus on CO activation of novel SPM metabolome and related mediators that down-regulate excessive PMN accumulation and stimulate clearance of both microbes and cellular debris. Project 4 will test the following hypothesis: Local activation of tissue resolution programs by inhaled CO involves production of novel anti-inflammatory and pro-resolving lipid mediators that enhance the clearance of apoptotic cells and microbes. CO activates the production of the new genus of SPM including resolvins and lipoxins and reduces biosynthesis of proinflammatory lipid mediators. SPM and CO act together to govern responses required for limiting inflammation and enhancing microbial killing and resolution. To test this. Project 4 will address 4 specific aims: 1.Determine the impact of CO on biosynthesis of lipid mediators and SPM during acute inflammation. 2. SPM activation of hemeoxygenase- 1 (HO-1). 3. Impact of CO and SPM In resolution of sepsis and second organ l/R acute lung injury;and 4. LM-lipidomic profiling with sepsis vs. ALI patient library/bank. Project 4 will provide the groundwork to harness uncontrolled Inflammatory responses and lung injury to Impact clinical practice by providing direct evidence for novel interactions between CO and SPM activation of resolution programs.
Project 4 in this translational P01 will focus on identification of new therapeutic approaches needed for better treating sepsis by establishing the interactions between inhaled CO and lipid mediators in vivo. We will provide the groundwork to harness uncontrolled inflammatory responses in sepsis to improve clinical practice by providing direct evidence for novel interactions between CO and SPM and their ability to activate resolution.
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