Department of Infectious Diseases, Huashan Hospital of Fudan University, 12 Middle Urumqi Road, Shanghai, 200040, China.
Dig Dis Sci. 2013 Oct;58(10):2895-902. doi: 10.1007/s10620-013-2823-6. Epub 2013 Aug 23.
The underlying mechanisms of nonalcoholic steatohepatitis (NASH) are poorly understood, and little is known about hepatocellular apoptosis in NASH. Cyclooxygenase (COX)-2, the key enzyme in eicosanoid metabolism, is highly expressed in NASH. COX-2 can also regulate the release of mediators of inflammation, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6. The aim of our study was to evaluate the effects of COX-2 on hepatocellular apoptosis and the mechanism of the action in the pathogenesis of NASH in rats.
Sprague-Dawley rats were fed a high-fat diet (HFD) or standard diet for 8 and 12 weeks. COX-2 and cytokines expression in hepatic tissue and TNF-α and IL-6 levels in serum were measured at 8 and 12 weeks. Moreover, celecoxib (10 mg/kg body weight once a day) was administered to rats for 4 weeks to inhibit the expression of COX-2. Liver pathology was assessed by hematoxylin and eosin (H&E) stain and electron microscopy. Hepatocyte apoptosis was evaluated by TUNEL staining.
COX-2 messenger RNA and protein were highly expressed in livers of HFD rats and were correlated with the severity of steatohepatitis (R = 0.82, p < 0.01). COX-2 upregulation was preceded by increases in TNF-α and IL-6. The level of hepatocellular apoptosis was significantly higher in HFD rats than in the control rats. The hepatocellular apoptosis was suppressed by the inhibition of COX-2.
COX-2 may promote hepatocellular apoptosis by interacting with TNF-α and IL-6 in NASH in rats.
非酒精性脂肪性肝炎（NASH）的发病机制尚未完全阐明，NASH 中肝细胞凋亡的相关机制也知之甚少。环氧化酶（COX）-2 是花生四烯酸代谢中的关键酶，在 NASH 中高度表达。COX-2 还可以调节炎症介质如肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6 的释放。本研究旨在评估 COX-2 在 NASH 大鼠肝细胞凋亡中的作用及其作用机制。
Sprague-Dawley 大鼠分别给予高脂饮食（HFD）或标准饮食 8 周和 12 周。分别在 8 周和 12 周时检测肝组织 COX-2 和细胞因子的表达以及血清 TNF-α和 IL-6 水平。此外，给予大鼠塞来昔布（10 mg/kg 体重，每天 1 次）4 周以抑制 COX-2 的表达。通过苏木精和伊红（H&E）染色和电子显微镜评估肝组织病理学。通过 TUNEL 染色评估肝细胞凋亡。
HFD 大鼠肝脏中 COX-2 信使 RNA 和蛋白表达水平较高，与脂肪性肝炎的严重程度呈正相关（R = 0.82，p < 0.01）。COX-2 的上调先于 TNF-α和 IL-6 的增加。HFD 大鼠的肝细胞凋亡水平明显高于对照组大鼠。COX-2 的抑制可抑制肝细胞凋亡。
COX-2 可能通过与 TNF-α和 IL-6 相互作用促进 NASH 大鼠的肝细胞凋亡。
