Mice Lacking Inducible Nitric Oxide Synthase are Not Resistant to Lipopolysaccharide-Induced Death

Nitric oxide produced by cytokine-inducible nitric oxide synthase (iNOS) is thought to be important in the pathogenesis of septic shock. To further our understanding of the role of iNOS in normal biology and in a variety of inflammatory disorders, including septic shock, we have used gene targeting...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1995-11, Vol.92 (23), p.10688-10692
Main Authors: Laubach, Victor E., Shesely, Edward G., Smithies, Oliver, Sherman, Paula A.
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Cell lines
Complementary DNA
Disease Models, Animal
DNA
Drug Resistance
Enzymes
Genetics
Genomics
Immunoblotting
Interferon-gamma - pharmacology
Lipopolysaccharides - toxicity
Macrophages
Macrophages, Peritoneal - enzymology
Mice
Mice, Mutant Strains
Molecular Sequence Data
Mortality
Nitrates - blood
Nitric Oxide Synthase - deficiency
Nitric Oxide Synthase - genetics
Nitrites
Nitrites - blood
Nitrogen Oxides - blood
Oxides
Recombination, Genetic
RNA, Messenger - analysis
Rodents
Septic shock
Shock, Septic - enzymology
Shock, Septic - etiology
Shock, Septic - genetics
Stem Cells
Survival Analysis
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Summary:Nitric oxide produced by cytokine-inducible nitric oxide synthase (iNOS) is thought to be important in the pathogenesis of septic shock. To further our understanding of the role of iNOS in normal biology and in a variety of inflammatory disorders, including septic shock, we have used gene targeting to generate a mouse strain that lacks iNOS. Mice lacking iNOS were indistinguishable from wild-type mice in appearance and histology. Upon treatment with lipopolysaccharide and interferon γ, peritoneal macrophages from the mutant mice did not produce nitric oxide measured as nitrite in the culture medium. In addition, lysates of these cells did not contain iNOS protein by immunoblot analysis or iNOS enzyme activity. In a Northern analysis of total RNA, no iNOS transcript of the correct size was detected. No increases in serum nitrite plus nitrate levels were observed in homozygous mutant mice treated with a lethal dose of lipopolysaccharide, but the mutant mice exhibited no significant survival advantage over wild-type mice. These results show that lack of iNOS activity does not prevent mortality in this murine model for septic shock.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.92.23.10688