MICE LACKING INDUCIBLE NITRIC-OXIDE SYNTHASE ARE NOT RESISTANT TO LIPOPOLYSACCHARIDE-INDUCED DEATH
MICE LACKING INDUCIBLE NITRIC-OXIDE SYNTHASE ARE NOT RESISTANT TO LIPOPOLYSACCHARIDE-INDUCED DEATH
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DOI：
10.1073/pnas.92.23.10688
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发表时间：
1995-11-07
影响因子：
11.1
通讯作者：
SHERMAN, PA
中科院分区：
文献类型：
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作者：
LAUBACH, VE;SHESELY, EG;SHERMAN, PA
细胞因子诱导型一氧化氮合酶 (iNOS) 产生的一氧化氮被认为在感染性休克的发病机制中很重要。为了进一步了解 iNOS 在正常生物学和各种炎症性疾病（包括败血性休克）中的作用，我们使用基因靶向来产生缺乏 iNOS 的小鼠品系。缺乏 iNOS 的小鼠在外观和组织学上与轻度型小鼠没有区别。在用脂多糖和干扰素γ处理后，来自突变小鼠的腹膜巨噬细胞不产生一氧化氮（在培养基中测量为亚硝酸盐）。此外，通过免疫印迹分析或 iNOS 酶活性，这些细胞的裂解物不含有 iNOS 蛋白。在 Northern 总 RNA 分析中，没有检测到正确大小的 iNOS 转录物。在用致死剂量的脂多糖处理的纯合突变小鼠中，没有观察到血清亚硝酸盐和硝酸盐水平增加，但突变小鼠与野生型小鼠相比没有表现出显着的生存优势。这些结果表明，iNOS活性的缺乏并不能防止这种败血性休克小鼠模型的死亡。
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,,ve have used gene targeting to generate a mouse strain that lacks iNOS. Mice lacking iNOS were indistinguishable from mild-type mice in appearance and histology. Upon treatment with lipopolysaccharide and interferon gamma, 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.