NITRIC OXIDE AS AN INDICATOR AND MEDIATOR OF AIRWAY INFLAMMATION

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Nitric oxide (NO) is a multifunctional biological mediator that has been implicated as an active participant in both the proinflammatory and the bronchodilator biology of asthma. As a proinflammatory mediator, NO can mediate airway epithelial tissue damage, probably by virtue of its oxidation to peroxynitrite, OONO, which is a highly toxic anion. NO may also function in a homeostatic role with both NO and stabilized forms of NO, such as nitrosothiols, mediating airway relaxation and inhibiting bronchovascular leak. It has been established that the mixed expired air recovered from nonasthmatic individuals. In individuals with asthma, treatment with glucocorticoid but not with bronchodilator or bronchoconstrictor drugs, results in a decrease in mixed expired NO levels. These observations prompt us to offer the following hypothesis: NO produced enzymatically by the airway serves both as an indicator of the inflammatory microenvironment of the airway and as a mediator of this inflammation in such a way as to promote airway obstruction and hyperresponsiveness. To test this hypothesis we propose to pursue 3 specific aims. In the first specific aim we will determine the relationship between lung function and mixed expired NO levels in a cohort of patients with moderate asthma in the period following withdrawal from treatment with inhaled glucocorticoids. If our hypothesis is correct, we expect to observe increases in the level of NO in mixed expired air, which will precede decrements in lung function. On a second cohort of patients airway biopsies will be obtained and analyzed to determine which cells change their phenotype as a result of the steroid withdrawal. In the third specific aim we will test the hypothesis that the microenvironmental availability o NO contributes to changes in airway responses and responsiveness following bronchoprovocation with inhaled allergen. To test this hypothesis we will examine the effects of inhibiting the enzymatic production of NO in the airways, by using an inhaled NOS inhibitor, on NO production and lung function. In our third specific aim we will test this hypothesis that endogenously produced NO serves as a mediator of airway obstruction and hyperresponsiveness in chronic stable asthma by determining the effects of treatment with an inhaled NO synthase inhibitor on expired levels of NO, airway obstruction, and airway responsiveness. Together the data obtained will allow us to determine if mixed expired NO is a premonitory indicator of asthma exacerbation and if the NO itself actually participates in the inflammatory process as a pro-phlogistic molecule.