Nitric oxide production in experimental gram-negative infection: studies with cytokine receptor-deficient mice.
Overproduction of nitric oxide (NO) upon expression of inducible NO synthase (iNOS) may be responsible for refractory hypotension in septic shock. Whereas high levels of NOS activity have been documented in experimental models of endotoxemia or intravenous challenge with Escherichia coil, much less is known concerning tissue models of Gram-negative infection. We examined NO production (measured as the accumulation of plasma NO3- + NO2-) in a murine model of Gram-negative peritonitis. Plasma NO3- + NO2- increased progressively from 25 microM to peak levels of 50-150 microM 24 h after intraperitoneal challenge with E. coli 0111:B4, similar to values reported for septic shock patients. Treatment of infected mice with NG-monomethyl-L-arginine, an inhibitor of NOS activity, resulted in the efficient inhibition of NO3- + NO2- production. In order to evaluate the roles of interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF-alpha) in the induction of NO synthesis in murine peritonitis, mice deficient in the respective cytokine receptors were studied. In control in vitro experiments, macrophages from IFN-gammaR- or TNFR55-deficient mice, while failing to respond to IFN-gamma or TNF-alpha, respectively, produced high levels of NO under appropriate stimulation. When challenged intraperitoneally with E. coli, IFN-gammaR- or TNFR55-deficient mice exhibited similar levels of bacteremia and NO production as their wild-type controls. These data thus suggest that enhanced NO production during focal Gram-negative infection may occur in the absence of signaling through either IFN-gammaR or TNFR55.
Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. dleroy@hola.hospvd.ch
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Le Roy
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Heumann
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Glauser
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Mauël
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Smith
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Betz Corradin
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000378:metabolism*; D010538:Peritonitis / Q000378:metabolism* / Q000382:microbiology; D018121:Receptors, Cytokine / Q000172:deficiency* / Q000235:genetics; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D018805:Sepsis / Q000378:metabolism*; D000096743:Interferon gamma Receptor
D015703:Antigens, CD; D009569:Nitric Oxide; D018121:Receptors, Cytokine; D017471:Receptors, Interferon; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D000096743:Interferon gamma Receptor