Role of inducible nitric oxide synthase in endotoxin-induced acute lung injury.
The role of nitric oxide (NO) in lung injury remains unclear. Both beneficial 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 knockout 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 measuring lactate dehydrogenase activity in the bronchoalveolar lavage, pulmonary 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 extensive nitrotyrosine staining in large airway and alveolar epithelium, macrophages, and pulmonary vascular cells. This was accompanied by induction of iNOS protein and increased lung nitric oxide synthase activity. By comparison, LPS injection in iNOS knockout mice elicited no iNOS induction and no significant 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 lung injury than are wild-type mice.
Kristof
A S
AS
Critical Care and Respiratory Divisions, Department of Medicine, Royal Victoria Hospital and Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada.
Goldberg
P
P
Laubach
V
V
Hussain
S N
SN
D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D001980:Bronchi / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004396:Coloring Agents; D004195:Disease Models, Animal; D004731:Endotoxins / Q000009:adverse effects*; D004848:Epithelium / Q000473:pathology; D004926:Escherichia coli; D005260:Female; D005500:Follow-Up Studies; D007527:Isoenzymes / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008168:Lung / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D009929:Organ Size; D011650:Pulmonary Alveoli / Q000473:pathology; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000209:etiology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D014665:Vasodilator Agents / Q000494:pharmacology
D004396:Coloring Agents; D004731:Endotoxins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D014665:Vasodilator Agents; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse