Molecular mechanisms of increased nitric oxide (NO) in asthma: Evidence for transcriptional and post-translational regulation of NO synthesis

Evidence supporting increased nitric oxide (NO) in asthma is substantial, a lthough the cellular and molecular mechanisms leading to increased NO are n ot known. Here, we provide a clear picture of the events regulating NO synt hesis in the human asthmatic airway in vivo. We show that human airway epit helium has abundant expression of NO synthase II (NOSII) due to continuous transcriptional activation of the gene in vivo. Individuals with asthma hav e higher than normal NO concentrations and increased NOSII mRNA and protein due to transcriptional regulation through activation of Stat1, NOSII mRNA expression decreases in asthmatics receiving inhaled corticosteroid, treatm ent effective in reducing inflammation in asthmatic airways. In addition to transcriptional mechanisms, post-translational events contribute to increa sed WO synthesis. Specifically, high output production of NO is fueled by a previously unsuspected increase in the NOS substrate, L-arginine. in airwa y epithelial cells of asthmatic individuals. Finally, nitration of proteins in airway epithelium provide evidence of functional consequences of increa sed NO. In conclusion, these studies define multiple mechanisms that functi on coordinately to support high level NO synthesis in the asthmatic airway. These findings represent a crucial cornerstone for future therapeutic stra tegies aimed at regulating NO synthesis in asthma.