Morio L A, Chiu H, Sprowles K A, Zhou P, Heck D E, Gordon M K, Laskin D L
Environmental and Occupational Health Sciences Institute, Rutgers University and the University of Medicine and Dentistry of New Jersey- Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
Toxicol Appl Pharmacol. 2001 Apr 1;172(1):44-51. doi: 10.1006/taap.2000.9133.
Macrophages are known to release a number of different inflammatory mediators with cytotoxic potential. In the present studies we analyzed the role of two macrophage-derived mediators, tumor necrosis factor-alpha (TNF-alpha) and nitric oxide, in liver injury induced by carbon tetrachloride (CCl4). Treatment of mice with CCl4 resulted in a dose- and time-dependent induction of centrilobular hepatic necrosis. This was observed within 12 h with 0.3 ml/kg CCl4 and was correlated with increases in serum transaminase levels. CCl4 administration also caused increases in hepatic TNF-alpha mRNA expression and serum TNF-alpha levels, as well as inducible nitric oxide synthase (NOS II) protein expression in the liver. To study the role of TNF-alpha and nitric oxide in hepatotoxicity, we used knockout mice lacking the gene for the 55-kDa TNF-alpha receptor (TNFR1/p55), the TNF-alpha cytokine, or NOS II. We found that CCl4 was significantly less effective in inducing hepatotoxicity in mice lacking TNFR1/p55 or the TNF-alpha cytokine. In contrast, CCl4-induced liver injury was increased in knockout mice lacking the gene for NOS II. This was associated with an increase in hepatic TNF-alpha mRNA expression and serum TNF-alpha levels. These data suggest that the hepatoprotective effects of nitric oxide in this model may be due in part to inhibition of TNF-alpha.
已知巨噬细胞会释放多种具有细胞毒性潜力的不同炎症介质。在本研究中，我们分析了两种巨噬细胞衍生介质——肿瘤坏死因子-α（TNF-α）和一氧化氮——在四氯化碳（CCl4）诱导的肝损伤中的作用。用CCl4处理小鼠会导致小叶中央性肝坏死呈剂量和时间依赖性诱导。在给予0.3 ml/kg CCl4后12小时内即可观察到这种情况，并且与血清转氨酶水平升高相关。给予CCl4还会导致肝脏中TNF-α mRNA表达和血清TNF-α水平升高，以及肝脏中诱导型一氧化氮合酶（NOS II）蛋白表达增加。为了研究TNF-α和一氧化氮在肝毒性中的作用，我们使用了缺乏55 kDa TNF-α受体（TNFR1/p55）基因、TNF-α细胞因子或NOS II的基因敲除小鼠。我们发现，CCl4在缺乏TNFR1/p55或TNF-α细胞因子的小鼠中诱导肝毒性的效果明显较差。相反，在缺乏NOS II基因的基因敲除小鼠中，CCl4诱导的肝损伤增加。这与肝脏中TNF-α mRNA表达和血清TNF-α水平升高有关。这些数据表明，在该模型中一氧化氮的肝保护作用可能部分归因于对TNF-α的抑制。
