Severe asthma affects 5-10% of asthmatics. It is associated with a poor quality of life, high risk for mortality, and accounts for a disproportionate share of the economic cost related to asthma. It is characterized by persistent airway inflammation despite corticosteroid therapy. Further, this inflammatory process is notable for a marked neutrophilia that differs from the eosinophil predominant inflammation characteristic of mild-moderate asthma. Lipoxins and epi-lipoxins are a class of small endogenous molecules that downregulate inflammatory responses including mobilization of neutrophils and eosinophils. They can be produced by cells in the lung and we have shown variability among asthmatics in their ability to synthesize these molecules. In view of the character of airway inflammation in severe asthma, and the known properties of the lipoxins, we hypothesize the following: In patients with mild-moderate asthma, lipoxins and 15-epi-lipoxins function as endogenous counterregulatory signals that dampen airway inflammation. In a subset of patients with severe asthma, defective counterregulatory signaling by this pathway accounts for persistent inflammation. To explore the role of these counter-regulatory molecules in severe asthma, we propose four Specific Aims: 1. Identify and characterize patients with severe asthma and a matched cohort with mild-to-moderate asthma; (2) Characterize LX and 15-epi-LX biosynthesis and receptor expression in severe asthma; (3) Determine if DNA sequence variants in genes of the LX and 15-epi-LX counterregulatory pathways are associated with asthma severity; and (4) Examine the functional significance of polymorphisms in candidate genes associated with asthma severity. We will draw on the complementary expertise of our investigators, who have collaborated on a variety of projects related to asthma, on the established asthma recruitment and phenotyping resources available at this site through the Asthma Clinical Research Network and on the genomic resources available through the Program in Genomic Applications, and the Pharmacogenetics Research Network. Elucidation of the roles played by lipoxins and epi-lipoxins in severe asthma and the genetic basis for differences in this counter-regulatory pathway among individuals would enhance our understanding of the pathogenesis of severe asthma. Such information may ultimately lead to new therapeutic strategies.
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