Inhibition of neuronal nitric oxide synthase in ovine model of acute lung injury

Both the positive and negative aspects of nitric oxide have been extensively described in previous studies. Among the three isoforms of the nitric oxide synthase (NOS), constitutive NOS (endothelial and neuronal) is believed to have ben eficial effects, such as maintaining normal homeostasis (1, 2). In contrast, inducible NOS (iNOS) is responsible for the injurious effects nitric oxide (NO) under certain circumstances (3). However, recent studies (4–6), including our own work (7, 8), provide evidence that neuronal NOS (nNOS) may play a profound role in the pathophysiology of organ dysfunction in various pathologic conditions such as Gram-negative sepsis (8). The findings that all NOS isoforms are expressed in lung tissue, and nNOS-derived NO accounts for 40% of exhaled NO (9) strongly supports the hypothesis that nNOS may potentially contribute to pathologic alterations. Pulmonary dysfunction and systemic hypoxemia with subsequent organ hypoxia is one of the crucial complications that determines the outcome for fire victims. A number of reports have previously described various pathologic factors, such as excessive NO, involved in the pathogenesis of multiple organ dysfunctions, including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in burn trauma (10). Using different iNOS inhibitors we have previously reported the important role of iNOS-associated NO in the pathophysiology of burn and smoke inhalation-induced multiple organ dysfunction (11–13). In this study, we tested the hypothesis that inhibition of nNOS-derived NO would ameliorate ALI in sheep exposed to combined burn and smoke inhalation injury, using a specific and potent nNOS inhibitor, ZK 234238 (3-methyl-2-amino-6,7,8,9-tetrahydro[2,1b]-1,4-oxazine).