Effect of polyI:C cotreatment on halothane-induced liver injury in mice.
Effect of polyI:C cotreatment on halothane-induced liver injury in mice.
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DOI：
10.1002/hep.22585
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发表时间：
2009-01
期刊：
影响因子：
13.5
通讯作者：
Ju, Cynthia
中科院分区：
文献类型：
--
作者：
Cheng, Linling;You, Qiang;Yin, Hao;Holt, Michael;Franklin, Christopher;Ju, Cynthia
药物性肝损伤（DILI）是药物研发和临床实践中一个具有挑战性的问题。患者对DILI的易感性是多因素的，这使得这些反应难以预测和预防。临床观察表明，并发的细菌和病毒感染是决定患者发生药物不良反应易感性的一个重要风险因素，尽管其潜在机制尚不清楚。在本研究中，我们使用病毒RNA模拟物（聚肌苷酸 - 聚胞苷酸，polyI:C）来模拟病毒感染，并研究其对氟烷诱导的肝损伤的影响。尽管用polyI:C预处理小鼠由于其对氟烷代谢的抑制作用而减轻了氟烷的肝毒性，但后处理显著加剧了肝损伤，肝细胞凋亡明显高于单独用polyI:C或单独用氟烷处理的小鼠。泛半胱天冬酶抑制剂z - VAD - fmk抑制了由polyI:C/氟烷后处理诱导的肝损伤，表明肝细胞凋亡增加导致了肝损伤的加剧。用polyI:C后处理还导致肝脏枯否细胞和自然杀伤细胞的活化，并上调多种促凋亡因子，包括肿瘤坏死因子 - α、NKG2D和FasL。这些因子可能在介导polyI:C诱导的肝细胞凋亡中起重要作用。这是第一项提供证据表明并发病毒感染可抑制CYP450活性并激活肝脏先天免疫系统产生促凋亡因子的研究。病原体可能根据感染时间减轻或加剧DILI。
Drug-induced liver injury (DILI) is a challenging problem in drug development and clinical practice. Patient susceptibility to DILI is multifactorial, making these reactions difficult to predict and prevent. Clinical observations have suggested that concurrent bacterial and viral infections represent an important risk factor in determining patient susceptibility to developing adverse drug reactions, although the underlying mechanism is not clear. In the present study, we employed the viral RNA mimetic (polyinosinic-polycytidylic acid, polyI:C) to emulate viral infection and examined its effect on halothane-induced liver injury. Although pre-treatment of mice with polyI:C attenuated halothane hepatotoxicity due to its inhibitory effect on halothane metabolism, post-treatment significantly exacerbated liver injury with hepatocellular apoptosis being significantly higher than that in mice treated with polyI:C alone or halothane alone. The pan-caspase inhibitor z-VAD-fmk suppressed liver injury induced by polyI:C/post-halothane co-treatment, suggesting that the increased hepatocyte apoptosis contributes to the exacerbation of liver injury. Post-treatment with polyI:C also caused activation of hepatic Kupffer cells and natural killer cells and up-regulated multiple pro-apoptotic factors, including tumor necrosis factor-α, NKG2D and FasL. These factors may play important roles in mediating polyI:C-induced hepatocyte apoptosis. This is the first study to provide evidence that concurrent viral infection can inhibit CYP450 activities and activate the hepatic innate immune system to pro-apoptotic factors. DILI may be attenuated or exacerbated by pathogens depending on the time of infection.
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影响因子：
158.5
作者：
COOPMAN, SA;JOHNSON, RA;STERN, RS
通讯作者：
STERN, RS
影响因子：
3.8
作者：
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9.8
作者：
GHANTOUS, HN;FERNANDO, JL;BRENDEL, K
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BRENDEL, K
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29.4
作者：
Liu, ZX;Govindarajan, S;Kaplowitz, N
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Kaplowitz, N
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4.1
作者：
Ju, C;Reilly, TP;Pohl, LR
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