The long range goal of this proposal is to improve the efficacy and utility of inhaled nitric oxide as a selective pulmonary vasodilator in cardiopulmonary disease. In addition to relaxing tone in the pulmonary circulation, NO alternates platelet aggregation and scavenge superoxide radicals. The applicant also plans to investigate whether NO exerts its beneficial effects by the cGMP signal transduction pathway. A variety of relevant and important techniques will be employed, including endothelial, neuronal and inducible NOS knockout mice, complement activation, signal transduction pathway analysis, and application of inhaled NO to thrombin-induced, hyperoxic, and complement mediated forms of lung injury. There are 3 specific aims:
Specific Aim 1 will investigate the basis for the lack of response to inhaled NO in 35% of the patients given this treatment. The applicant plans to investigate the NO-cGMP signal transduction pathway, role of phosphodiesterase (PDE) activity, influence of endotoxin, feedback inhalation of NO on NOS activity and induction of tachyphylaxis, and compare several of these mechanisms in rats to sheep.
Specific Aim 2 is to investigate the interactions of inhaled NO with intrapulmonary NOS activity. This involves studying the three isoforms of NOS and whether absence of any one form via knockout mice alters the response to inhaled NO and to bacterial endotoxin. The applicant also plans to study exhaled NO as a marker of pulmonary NOS activity in each NOS deficient knockout mouse.
Specific Aim 3 is to determine how both endogenously released and exogeneously administered NO influences the resonse of the injured lung. Three forms of lung injury will be used (i.e., hyperoxia, thrombin, and complement activation).
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