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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.