Lack of inducible nitric oxide synthase leads to increased hepatic apoptosis and decreased fibrosis in mice after chronic carbon tetrachloride administration
Lack of inducible nitric oxide synthase leads to increased hepatic apoptosis and decreased fibrosis in mice after chronic carbon tetrachloride administration
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DOI：
10.1002/hep.22278
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发表时间：
2008-06-01
期刊：
影响因子：
13.5
通讯作者：
Mezey, Esteban
中科院分区：
文献类型：
--
作者：
Aram, Ghazaleh;Potter, James J.;Mezey, Esteban
一氧化氮(NO)在肝损伤和肝纤维化中的作用尚不清楚。本研究旨在探讨诱导型一氧化氮合酶缺乏症(iNOS(-/-))对四氯化碳(CCl4)慢性染毒所致小鼠肝损伤和肝纤维化的影响。野生型(WT)或诱导型(-/-)小鼠接受为期8周的两周一次的CCl4注射，而对照组给予等容量的橄榄油注射。CCl4后，iNOS(-/-)组小鼠血清转氨酶水平低于WT组，这与肝组织学坏死减少有关。与WT小鼠相比，iNOS(-/-)组细胞凋亡率增加，星状细胞数量减少，纤维化程度减轻。α(1)(I)胶原信使RNA(MRNA)在CCl4后在NW显著增加，而在iNOS(-/-)小鼠中增加的幅度明显较小。CCl4后，WT组小鼠肝基质金属蛋白酶-9(MMP9)和MMP2mRNA的表达水平明显高于iNOS(-/-)组。此外，组织抑制物金属蛋白酶1(TIMP-1)mRNA在CCl4后，NW组比iNOS(-/-)组增加的幅度要大得多(P<；0.05)。然而，免疫印迹检测显示，CCl4处理后，两组小鼠的MMP9和TIMP-1蛋白表达均有类似的增加。结论：NO对CCl4诱导的细胞凋亡有保护作用。在没有诱导型一氧化氮合酶的情况下，坏死减少，细胞凋亡增加，肝纤维化减轻。
The role of nitric oxide (NO) in liver injury and fibrosis is unclear. The purpose of this study was to determine whether inducible NO synthase deficiency (iNOS(-/-)) affects liver injury and fibrosis produced in mice by chronic carbon tetrachloride (CCl4) administration. Wildtype (WT) or iNOS(-/-) mice were subjected to biweekly CCl4 injections over 8 weeks, whereas controls were given isovolumetric injections of olive oil. Serum aminotransferases were lower after CCl4 in the iNOS(-/-) than in the WT mice, which correlated with decreased necrosis on liver histology. There was increased apoptosis, a lower number of stellate cells, and a lesser degree of fibrosis after CCl4 in the iNOS(-/-) as compared with the WT mice. alpha(1)(I) collagen messenger RNA (mRNA) was markedly increased after CCl4 in the NW and to a significantly lesser extent in the iNOS(-/-) mice. Liver matrix metalloproteinase-9 (MMP-9) mRNA and MMP-2 mRNA were increased more in the WT than in the iNOS(-/-) mice after CCl4. Also tissue inhibitor metalloproteinase 1 (TIMP-1) mRNA was increased to a much greater extent in the NW than in the iNOS(-/-) mice after CCl4 (P < 0.05). However, MMP-9 and TIMP-1 protein, determined by western blot, were similarly increased after CCl4 in both groups of mice. Conclusion: NO protects against CCl4-induced apoptosis. In the absence of iNOS, there is decreased necrosis, increased apoptosis, and reduced liver fibrosis.