title: Lethality of endotoxin in mice genetically deficient in the respiratory burst oxidase, inducible nitric oxide synthase, or both.
abstract: Two classes of oxidants are thought to play a critical role in tissue damage in septic shock: reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI). Particular importance has been ascribed to peroxynitrite, a product arising from the reaction of nitric oxide with superoxide. A major source of ROI is the respiratory burst oxidase of neutrophils, eosinophils, monocytes, and macrophages. A major source of RNI is inducible nitric oxide synthase (iNOS), an enzyme expressed in leukocytes, hepatocytes, vascular smooth muscle cells, endothelium, and cardiac myocytes during inflammation. In previous studies using various mouse models of endotoxic shock, genetic deficiency of iNOS as a sole intervention did not consistently alter survival. Here, using Salmonella typhimurium endotoxic bacterial lipopolysaccharide (LPS) as a sole challenge, genetic deficiency of iNOS was associated with no protection or a reduction in survival, depending on the dose of LPS. Further, no protection from lethality was observed when LPS was injected into mice genetically deficient in the 91 kDa subunit of the respiratory burst oxidase (gp91phox) nor in mice genetically deficient in both gp91phox and iNOS (gp91phox-/-/NOS2-/- mice). For the latter experiments, mice were challenged either with S. typhimurium LPS alone or with inactivated bacille Calmette-Guerin (BCG) followed by Escherichia coli LPS. Deficiency of gp91phox impaired the inflammatory response to inactivated Propionobacterium acnes, rendering survival studies following priming with P. acnes difficult to interpret. Thus, in two models of endotoxic shock, major reductions in the ability to form nitric oxide or superoxide, alone or in combination, failed to improve survival.
authors.affiliation: Department of Microbiology & Immunology, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Nicholson
authors.forename: S R
authors.initials: SR
authors.lastname: Grobmyer
authors.forename: M U
authors.initials: MU
authors.lastname: Shiloh
authors.forename: J E
authors.initials: JE
authors.lastname: Brause
authors.forename: S
authors.initials: S
authors.lastname: Potter
authors.forename: J D
authors.initials: JD
authors.lastname: MacMicking
authors.forename: M C
authors.initials: MC
authors.lastname: Dinauer
authors.forename: C F
authors.initials: CF
authors.lastname: Nathan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000503:physiopathology; D004731:Endotoxins / Q000633:toxicity; D004926:Escherichia coli / Q000472:pathogenicity; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency / Q000235:genetics*; D019255:NADPH Oxidases; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D012486:Salmonella typhimurium / Q000472:pathogenicity; D012772:Shock, Septic / Q000235:genetics*; D015996:Survival Rate
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; C022709:superoxide-forming enzyme