Severe asthma affects 5-10% of asthmatics and is associated with a poor quality of life, excess morbidity and a disproportionate share of the economic costs related to asthma. It is characterized by persistent airway inflammation despite corticosteroid therapy. Lipoxins and 15-epi-lipoxins are a class of endogenous small molecules that are produced in the lung and downregulate inflammatory responses characteristic of the inflammation in severe asthma. Some individuals with severe asthma carry a defect in the generation of lipoxins, so excess inflammation in these individuals may result from decreased production of these protective mediators. Recently, inhibition of soluble expoxide hydrolase was demonstrated to increase production of lipoxins and 15-epi-lipoxins in lung inflammation. Soluble epoxide hydrolase converts arachidonic acid-derived epoxyeicosatrienoic acids (EETs) to their corresponding dihydroxy forms. Inhibition of soluble epoxide hydrolase leads to a relative increase in EETs and a shift in arachidonic acid metabolism that increases its enzymatic conversion to lipoxins and 15-epi-lipoxins. Potent inhibitors of soluble epoxide hydrolase are currently in clinical development, including a phase II trial for atherosclerosis. Taken together, there are multiple lines of evidence in murine and human model systems that would support a beneficial action for soluble epoxide hydrolase inhibition in asthma, but this has not been directly established. The proposed experiments will test the hypothesis that inhibition of soluble epoxide liydrolase will increase lipoxin generation in severe asthma. In CADET I, we propose to utilize samples of blood and bronchoalveolar lavage fluid from individuals with severe asthma for two specific aims to: }} Validate soluble epoxide hydrolase inhibition as a therapeutic target to increase lipoxin generation in asthmatic inflammation, and }} Develop a non-invasive method to identify the sub-population of severe asthma subjects that have low airway levels of lipoxins. The proposed experiments will set the stage for a clinical trial in CADET II that will test the benefits of a soluble epoxide hydrolase inhibitor in subjects with steroid resistant severe asthma and low lipoxin generation.
(See Instructions): Patients with severe asthma do not respond to anti-inflammatory controller therapy, including corticosteroids, and thus experience excess morbidity and a greater need for healthcare support. In this proposal, we will utilize samples collected in a funded, multicenter clinical trial of ninety subjects with severe asthma to (1) validate soluble epoxide hydrolase inhibition as a potential novel therapeutic target and (2) develop a non}} invasive method to identify individuals with severe asthma that are most likely to benefit from this therapy.
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