MICE LACKING INDUCIBLE NITRIC-OXIDE SYNTHASE ARE NOT RESISTANT TO LIPOPOLYSACCHARIDE-INDUCED DEATH

Nitric oxide produced by cytokine-inducible nitric oxide synthase (iNO S) 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,,ve have used gene targeting to generate a mouse strain that lacks iNOS. Mice l acking iNOS were indistinguishable from mild-type mice in appearance a nd histology. Upon treatment with lipopolysaccharide and interferon ga mma, peritoneal macrophages from the mutant mice did not produce nitri c oxide measured as nitrite in the culture medium. In addition, lysate s of these cells did not contain iNOS protein by immunoblot analysis o r iNOS enzyme activity. In a Northern analysis of total RNA, no iNOS t ranscript of the correct size was detected. No increases in serum nitr ite plus nitrate levels were observed in homozygous mutant mice treate d with a lethal dose of lipopolysaccharide, but the mutant mice exhibi ted no significant survival advantage over wild-type mice, These resul ts show that lack of iNOS activity does not prevent mortality in this murine model for septic shock.