Inflammation plays a central role in the pathogenesis of asthma. One important inflammatory mediator is nitric oxide (NO), a vasodilator of the bronchial circulation. Recent studies suggest that asthma may be a condition of decreased NO bioavailability. NO is produced by L-arginine (L-arg) by NO syntheses (NOS). It has been recently reported that a decreased L-arg bioavailability in asthmatic patients likely contributes to the NO deficiency in asthma. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, has been established as a novel cardiovascular risk factor and its accumulation has been reported in a variety of disorders. Although clinical and experimental evidence indicates that elevation of ADMA may cause a relative L-arg deficiency, no data are available on the relative ADMA levels in asthmatic patients. Therefore, the goal of this proposal is to determine the mechanism of ADMA's effects in epithelial cells and demonstrate an in vivo association between ADMA levels and the pathology of asthma using a murine model. Upon successful completion of this proposal, our expectation is that these studies will not only provide new insights into the pathology of asthma, but also potentially identify a novel factor in the development of this disease. [unreadable] [unreadable] [unreadable]