Lipid Mediators in Resolution of Asthma Exacerbations

Brigham And Women'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): The proposed experiments will test the hypothesis that in response to an asthma exacerbation, biosynthetic circuits are established in the airway for production of specific lipid mediators that promote resolution of airway inflammation and hyper-responsiveness. Although we are accustomed to viewing the increase in airway inflammation and hyper-responsiveness during asthma exacerbations as the result of an over-abundance of pro-inflammatory stimuli, an asthma exacerbation could also result from insufficient endogenous anti-inflammatory effectors. Lipid mediators, such as cysteinyl leukotrienes, are well appreciated to play important roles in asthma, but not all lipid mediators initiate inflammation. For example, lipoxins (LXs) are a distinct class of arachidonic acid-derived lipid mediators that regulate leukocyte trafficking and inhibit allergic airway inflammation and hyper-responsiveness. Thus, LXs are the initial members in a growing family of lipid mediators of anti-inflammation and resolution. In extrapulmonary tissues, intriguing tissue-protective actions have recently been assigned to newly identified lipid mediators derived from eicosapentaenoic acid and docosahexaenoic acid. In addition to triggering inflammation and bronchoconstriction, the notion that select endogenous lipid mediators are also generated to promote resolution of these airway responses would turn conventional thinking on its head, and identify these natural anti-inflammatory compounds as novel templates for rational drug design. To test our hypothesis, we propose four specific aims to determine: formation of novel lipid mediators in vivo during a murine experimental model of asthma exacerbation and resolution; the influence of select lipid mediators on human airway epithelial function; regulation of murine experimental asthma by specific, pro-resolving lipids; and generation of candidate pro-resolving lipid mediators during asthma exacerbation and resolution in humans. This proposal's specific aims are directed towards uncovering basic mechanisms in the pathobiology of resolution from asthma exacerbation.