In vivo inhibition of nuclear factor-kappa B activation prevents inducible nitric oxide synthase expression and systemic hypotension in a rat model of septic shock.
In vivo inhibition of nuclear factor-kappa B activation prevents inducible nitric oxide synthase expression and systemic hypotension in a rat model of septic shock.
复制标题
DOI：
10.4049/jimmunol.159.8.3976
复制
发表时间：
1997-10
影响因子：
4.4
通讯作者：
S. F. Liu;X. Ye;A. Malik
中科院分区：
文献类型：
--
作者：
S. F. Liu;X. Ye;A. Malik
在感染性休克大鼠模型中，我们研究了内毒素诱导的核因子-kappaB(NF-kappa B)激活在介导诱导型一氧化氮合酶(INOS)mRNA和蛋白表达以及全身动脉低血压中的作用。脂多糖(8 mg/kg静脉注射)在15min内，大鼠肺组织中的核因子-kappa B被激活，反应持续到4h，核因子-kappaB的激活先于诱导型一氧化氮合酶的表达。吡咯烷二硫代氨基甲酸酯(PDTC)是一种在细胞研究中有效的核因子-kappaB的抑制剂，可在体内阻止核因子-kappaB的激活，并减少iNOS mRNA的表达，并增加内毒素激活的iNOS活性。PDTC浓度为50、100、200 mg/kg时，iNOS基因表达分别减少20、46、48%，iNOS活性分别减少59、66、75%。随着PDTC浓度的增加，iNOS活性下降，血浆亚硝酸盐/硝酸盐浓度也出现类似的下降。PDTC对脂多糖引起的动脉血压下降也有保护作用。这些结果表明，核因子-kappaB的激活是介导内毒素诱导的iNOS表达和由此引起的全身性低血压的一个关键的体内调节机制。
We determined the in vivo function of LPS-induced nuclear factor-kappa B (NF-kappa B) activation in mediating inducible nitric oxide synthase (iNOS) mRNA and protein expression, and systemic arterial hypotension in a rat model of septic shock. LPS (8 mg/kg i.v.) challenge of rats activated NF-kappa B within 15 min in lung tissue, and the response persisted up to 4 h. NF-kappa B activation preceded the induction of iNOS mRNA. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappa B effective in cellular studies, prevented NF-kappa B activation in vivo and reduced iNOS mRNA expression and the increase in iNOS activity activated by LPS. At PDTC concentrations of 50, 100, and 200 mg/kg, the reductions of iNOS mRNA were 20, 46, and 48%, and the reductions in iNOS activity were 59, 66, and 75%, respectively. The PDTC concentration-dependent reductions in iNOS activity produced similar decreases in plasma nitrite/nitrate concentrations. PDTC also prevented the decrease in arterial blood pressure induced by LPS. These results demonstrate that activation of NF-kappa B is a critical in vivo regulatory mechanism mediating LPS-induced iNOS expression and the resultant systemic hypotension.