Savransky Vladimir, Bevans Shannon, Nanayakkara Ashika, Li Jianguo, Smith Philip L, Torbenson Michael S, Polotsky Vsevolod Y
Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA.
Am J Physiol Gastrointest Liver Physiol. 2007 Oct;293(4):G871-7. doi: 10.1152/ajpgi.00145.2007. Epub 2007 Aug 9.
Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (CIH) during sleep. OSA is associated with nonalcoholic steatohepatitis (NASH) in obese individuals and may contribute to progression of nonalcoholic fatty liver disease from steatosis to NASH. The purpose of this study was to examine whether CIH induces inflammatory changes in the liver in mice with diet-induced hepatic steatosis. C57BL/6J mice (n = 8) on a high-fat, high-cholesterol diet were exposed to CIH for 6 mo and were compared with mice on the same diet exposed to intermittent air (control; n = 8). CIH caused liver injury with an increase in serum ALT (461 +/- 58 U/l vs. 103 +/- 16 U/l in the control group; P < 0.01) and AST (637 +/- 37 U/l vs. 175 +/- 13 U/l in the control group; P < 0.001), whereas alkaline phosphatase and total bilirubin levels were unchanged. Histology revealed hepatic steatosis in both groups, with mild accentuation of fat staining in the zone 3 hepatocytes in mice exposed to CIH. Animals exposed to CIH exhibited lobular inflammation and fibrosis in the liver, which were not evident in control mice. CIH caused significant increases in lipid peroxidation in serum and liver tissue; significant increases in hepatic levels of myeloperoxidase and proinflammatory cytokines IL-1beta, IL-6, and CXC chemokine MIP-2; a trend toward an increase in TNF-alpha; and an increase in alpha1(I)-collagen mRNA. We conclude that CIH induces lipid peroxidation and inflammation in the livers of mice on a high-fat, high-cholesterol diet.
阻塞性睡眠呼吸暂停（OSA）在睡眠期间会导致慢性间歇性缺氧（CIH）。OSA与肥胖个体的非酒精性脂肪性肝炎（NASH）相关，并且可能促使非酒精性脂肪性肝病从脂肪变性发展为NASH。本研究的目的是检验CIH是否会在饮食诱导的肝脂肪变性小鼠中引起肝脏的炎症变化。将高脂、高胆固醇饮食的C57BL/6J小鼠（n = 8）暴露于CIH 6个月，并与相同饮食但暴露于间歇性空气的小鼠（对照组；n = 8）进行比较。CIH导致肝脏损伤，血清谷丙转氨酶（ALT）升高（461±58 U/L，对照组为103±16 U/L；P < 0.01）和谷草转氨酶（AST）升高（637±37 U/L，对照组为175±13 U/L；P < 0.001），而碱性磷酸酶和总胆红素水平未改变。组织学检查显示两组均有肝脂肪变性，在暴露于CIH的小鼠中，3区肝细胞的脂肪染色轻度加重。暴露于CIH的动物肝脏出现小叶炎症和纤维化，而对照组小鼠中不明显。CIH导致血清和肝组织中的脂质过氧化显著增加；肝脏中髓过氧化物酶和促炎细胞因子白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和CXC趋化因子巨噬细胞炎性蛋白-2（MIP-2）水平显著升高；肿瘤坏死因子-α（TNF-α）有升高趋势；α1（I）-胶原mRNA增加。我们得出结论，CIH会在高脂、高胆固醇饮食的小鼠肝脏中诱导脂质过氧化和炎症。
