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Transcript
Guest Lecture Monday, June 20th at 11:00 Hringsalur -Landspitali Dr. Bruce D. Levy Associate Professor of Medicine Harvard Medical School Omega-3 Fatty Acid-Derived Mediators of Resolution in Health and Airway Disease Abstract: Acute inflammation in the lung is fundamentally important to host defense, but chronic or excessive inflammation leads to several important respiratory diseases, including asthma. The resolution of inflammation is an active process. In health, cell-cell interactions at the onset of acute inflammation establish biosynthetic circuits for specific mediators that later serve as agonists to orchestrate a return to tissue homeostasis. Understanding how cells communicate and collaborate to generate anti-inflammatory, pro-resolution molecules and their counter-regulatory signalling pathways are providing new insights into the molecular pathophysiology of lung disease and opportunities for the therapeutic intervention. Evidence will be presented for resolvins as select members of a growing family of pro-resolving and anti-inflammatory lipid-derived mediators that can regulate airway inflammation and promote host defense. E-series resolvins are enzymatically derived from the essential omega-3 fatty acid eicosapentaenoic acid. Resolvin E1 (RvE1) displays protective actions in adaptive immune responses. To promote resolution of allergic airway responses, including inflammation, mucus metaplasia and hyper-reactivity, RvE1 decreased production of the pro-inflammatory cytokines IL-23, IL-6 and IL-17, increased production of the counter-regulatory mediators IFN and LXA4 and promoted natural killer cell-mediated clearance of activated, antigen-specific T cells. The impact of RvE1 on host defense was tested in a model of aspiration pneumonia. Mice received hydrochloric acid into the left lung followed by the enteric pathogen E. coli. Intravenous administration of RvE1 (~0.005 mg/kg) prior to acid injury selectively decreased lung neutrophil accumulation by 55% and enhanced clearance of E. coli. RvE1 significantly decreased lung tissue levels of several pro-inflammatory chemokines and cytokines. In addition, RvE1 treated animals had a marked improvement in survival. These findings in experimental aspiration pneumonia have uncovered additional protective roles for RvE1 in pathogen-mediated inflammation that are both anti-inflammatory for neutrophils and protective for host defense, suggesting that RvE1 represents a first candidate for a novel therapeutic strategy that harnesses natural resolution mechanisms.