Specialized Pro-Resolving Mediators in Asthma

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Abstract The proposed experiments will test the hypothesis that specialized pro-resolving mediators (SPMs) and cysteinyl-containing SPMs (CysSPMs) are produced in the lung to counter-regulate pro-phlogistic responses and to promote resolution of lung inflammation, in part via activation of a pro-resolving subset of eosinophils. Although we are accustomed to viewing the increase in airway inflammation and hyper-responsiveness in asthma as the result of an over-abundance of pro-inflammatory stimuli, the severity and duration of an asthma exacerbation could also result from insufficient endogenous anti-inflammatory effectors. Cysteinyl leukotrienes are well appreciated to play pro-phlogistic roles in asthma, but not all lipid mediators initiate inflammation. There are now several families of specialized pro-resolving mediators (SPM) that have been identified and characterized in acute inflammation. These protective mediators are enzymatically derived from essential fatty acids and serve as agonists at specific receptors to transduce cell type specific functional responses, including in eosinophil subsets that are relevant in asthma. With several drugs already developed to block CysLT formation or action, the notion that select endogenous lipid-derived mediators are generated to promote resolution of asthmatic airway responses would turn conventional thinking on its head and identify CysSPMs as natural pro-resolving mediators and novel templates for drug design. To test our hypothesis, we propose three specific aims to:  Determine lung SPM and CysSPM production in acute and chronic allergic lung inflammation,  Establish SPM and CysSPM actions in the resolution of lung inflammatory responses, and  Define roles for lung eosinophil subsets in promoting inflammation resolution. This proposal’s specific aims are directed towards uncovering basic mechanisms that govern the resolution of allergic airway responses in health and disease.