Chronic intermittent hypoxia and acetaminophen induce synergistic liver injury in mice.
Chronic intermittent hypoxia and acetaminophen induce synergistic liver injury in mice.
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DOI：
10.1113/expphysiol.2008.044883
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发表时间：
2009-02
影响因子：
2.7
通讯作者：
Polotsky VY
中科院分区：
文献类型：
--
作者：
Savransky V;Reinke C;Jun J;Bevans-Fonti S;Nanayakkara A;Li J;Myers AC;Torbenson MS;Polotsky VY
阻塞性睡眠呼吸暂停（OSA）导致睡眠期间慢性间歇性缺氧（CIH）。阻塞性睡眠呼吸暂停与肝损伤有关。对乙酰氨基酚（APAP）是最常用的药物之一，具有肝毒性。本研究的目的是研究CIH是否会增加慢性APAP治疗引起的肝损伤、肝脏氧化应激和炎症。C57BL/6J小鼠暴露于CIH或间歇空气（IA） 4周。两组小鼠每天分别腹腔注射APAP （200 mg/kg）或生理盐水。联用CIH和APAP引起肝损伤，血清丙氨酸转氨酶、天冬氨酸转氨酶（AST）、γ谷氨酰转氨酶和总胆红素水平显著升高，而CIH仅引起血清AST水平升高。单独使用APAP不影响血清肝酶水平。组织病理学显示，暴露于CIH和APAP的小鼠肝脏坏死和细胞凋亡增加，而其他所有组的肝脏保持完整。暴露于CIH和APAP的小鼠表现出肝脏谷胱甘肽减少，同时硝基酪氨酸水平增加5倍，表明肝细胞中形成了有毒的过氧亚硝酸盐。单独使用APAP或CIH对谷胱甘肽或硝基酪氨酸均无影响。CIH和APAP联用引起促炎趋化因子、单核细胞趋化蛋白-1和巨噬细胞炎症蛋白-2的显著增加，而单独暴露于CIH或APAP的小鼠未观察到这一现象。我们得出结论，CIH和慢性APAP治疗可导致协同性肝损伤，这可能对OSA患者具有临床意义。
Obstructive sleep apnea (OSA) leads to chronic intermittent hypoxia (CIH) during sleep. OSA has been associated with liver injury. Acetaminophen (APAP) is one of the most commonly used drugs, which has known hepatotoxicity. The goal of the present study was to examine whether CIH increases liver injury, hepatic oxidative stress and inflammation induced by chronic APAP treatment. C57BL/6J mice were exposed to CIH or intermittent air (IA) for 4 weeks. Mice in both groups were treated with intraperitoneal injections of either APAP (200 mg/kg) or normal saline daily. A combination of CIH and APAP caused liver injury with marked increases in serum alanine aminotransferase, aspartate aminotransferase (AST), gamma glutamyl transferase and total bilirubin levels, whereas CIH alone induced only elevation in serum AST levels. APAP alone did not affect serum levels of liver enzymes. Histopathology revealed hepatic necrosis and increased apoptosis in mice exposed to CIH and APAP, whereas the liver remained intact in all other groups. Mice exposed to CIH and APAP exhibited decreased hepatic glutathione in conjunction with a five-fold increase in nitrotyrosine levels, suggesting formation of toxic peroxynitrite in hepatocytes. APAP or CIH alone had no effect on either glutathione or nitrotyrosine. A combination of CIH and APAP caused marked increases in pro-inflammatory chemokines, monocyte chemoattractant protein-1 and macrophage inflammatory protein-2, which were not observed in mice exposed to CIH or APAP alone. We conclude that CIH and chronic APAP treatment lead to synergistic liver injury, which may have clinical implications for patients with OSA.
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影响因子：
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Hinson, JA;Pike, SL;Mayeux, PR
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