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Role of macrophage-derived nitric oxide in endotoxin lethality in mice

Department of Microbiology, Molecular Genetics and Immunology, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA

S.-Y. Hao

Department of Microbiology, Molecular Genetics and Immunology, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA

D.C. Morrison

Department of Microbiology, Molecular Genetics and Immunology, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA

J.L. Pace

Department of Microbiology, Molecular Genetics and Immunology, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA

Endotoxic lipopolysaccharides (LPS) mediate lethality in mice by a complex inflammatory process involving the production of multiple mediators, including tumor necrosis factor- (TNF-) and nitric oxide (NO). The present study had two objectives: (i) to determine the extent to which TNF- contributes to the induction of NO production by mouse macrophages activated with LPS in vitro; and (ii) to assess the contribution of macrophage-derived NO to the pathogenesis of endotoxin shock in mice. The studies reported here show that the synthetic adenyl carbocyclic nucleoside 9-[(1S,3R)-cis-cyclopentan-3-ol]adenine (cPA) inhibited TNF-, but not NO, production by thioglycollate-elicited peritoneal macrophages that were activated with either LPS alone, LPS + interferon- (IFN-) or IFN- + TNF-. The expression of cytoplasmic TNF- in LPS + IFN--activated cells was similarly inhibited by cPA, whereas the appearance of inducible NO synthase was unaffected by the compound. Of significance, pretreatment of mice with a single injection of cPA protected the animals against subsequent LPS challenge in two models of endotoxin lethality. These results suggest that macrophage-derived NO, induced by LPS, may not be an essential mediator of the lethal effects of endotoxin. Further, the results of these studies suggest that TNF--induced NO production by tissue macrophages also may not be an essential contributing factor in the pathogenesis of lethality induced by endotoxin in mice.

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