Asthma has a large impact on the children of our society. It is among the most common chronic diseases of childhood and is the leading cause of absenteeism from school. The reasons that more children are having recurrent episodes of wheezing and some have asthma while others do not are unknown. There is increasing evidence that differences in innate immune responses among children can determine which will have recurrent wheezing and asthma. While many studies have focused on the factors that initiate innate immune responses there are relatively few studies of the down stream factors that cause abnormal airway responses. We present evidence that eicosanoid mediators are part of the innate immune response and can function as its effector arm for allergic responses. The ability of leukotrienes and prostaglandins to produce central features of the asthma phenotype is well described and there is emerging evidence that lipoxins facilitate restoration of allergic changes in the airways. We tender the hypothesis that the balance of eicosanoid expression in the airways during early-life wheezing illness and the genetically determined capacity to respond will predict recurrent wheezing. Moreover, we propose that an intervention to restore a more normal tissue response to this imbalance will reduce symptoms of early life wheezing and subsequent recurrent episodes. To test these hypotheses we propose the following 3 specific aims: ? ? 1. To serially measure the airway eicosanoid profiles of a population of children 3 months to 3 years of age who seek physician care for a wheezing illness and determine their association with subsequent development of the asthma phenotype ? 2. To identify members of this population who bear genetic variants in eicosanoid metabolic and response pathways and assess the effects of the variants on the propensity for recurrent wheezing. ? 3. To determine the effects of intervention during an early-life wheezing illness with a cysteinylleukotriene-1 receptor antagonist on the duration of symptoms and the rate of recurrent wheezing and expression of associated features of the asthma phenotype. ? ?
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