Role of inducible nitric oxide synthase in endotoxin-induced acute lung injury

The role of nitric oxide (NO) in lung injury remains unclear. Both benefici al and detrimental roles have been proposed. In this study, we used mutant mice lacking the inducible nitric oxide synthase (iNOS) to assess the role of this isoform in sepsis-associated lung injury. Wild-type and iNOS knocko ut mice were injected with either saline or Escherichia coli endotoxin (LPS ) 25 mg/kg and killed 6, 12, and 24 h later. Lung injury was evaluated by m easuring lactate dehydrogenase activity in the bronchoalveolar lavage, pulm onary wet/dry ratio, and immunostaining for nitrotyrosine formation. In the wild-type mice, LPS injection elicited more than a 3-fold rise in lactate dehydrogenase activity, a significant rise in lung wet/dry ratio and extens ive nitrotyrosine staining in large airway and alveolar epithelium, macroph ages, and pulmonary vascular cells. This was accompanied by induction of iN OS protein and increased lung nitric oxide synthase activity. By comparison , LPS injection in iNOS knockout mice elicited no iNOS induction and no sig nificant changes in lung NOS activity, lactate dehydrogenase activity, lung wet/dry ratio, or pulmonary nitrotyrosine staining. These results indicate that mice deficient in iNOS gene are more resistant to LPS-induced acute l ung injury than are wild-type mice.