Tu Chuan-Tao, Guo Jin-Sheng, Wang Manner, Wang Ji-Yao
Division of Digestive Diseases, Zhong Shan Hospital, Department of Internal Medicine, Shanghai Medical Collage, Fu Dan University, Shanghai, China.
J Gastroenterol Hepatol. 2007 Jun;22(6):877-84. doi: 10.1111/j.1440-1746.2007.04867.x.
Upregulation of cyclooxygenase-2 (COX-2), an inducible enzyme that is actively involved in inflammation and wound healing, has been found in cirrhotic livers. The aim of this study was to investigate the effects of selective inhibition of COX-2 on the development of liver cirrhosis and portal hypertension in rats.
Liver cirrhosis was induced by carbon tetrachloride (CCl(4)) in Sprague-Dawley rats. Rofecoxib, a highly selective COX-2 inhibitor, was orally administered to rats at a dose of 10 mg/kg/day. Portal pressure was measured at 8 weeks post CCl(4) administration with the catheterization method followed by the harvesting of liver samples. Liver histopathology was analyzed with hematoxylin and eosin and Masson's trichrome staining. The activated, alpha smooth muscle actin (alpha-SMA) positive hepatic stellate cells (HSCs) and the protein levels of collagen types I, III, IV, as well as laminin and two fibrogenic mediators, vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) in the livers, were detected with immunohistochemical staining and western blot methods, respectively. The level of hepatic thromboxane B(2) (TXB(2)), a potent vasoconstrictive substance derived from COX, was measured with enzyme immunoassay.
Oral administration of rofecoxib decreased portal pressure in rats that were treated with CCl(4) for 8 weeks. This was associated with a marked reduction in collagen accumulation and TXB(2) level in the rat livers. In addition, rofecoxib administration was found to reduce the number of activated HSCs and to downregulate hepatic protein levels of three detected types of collagen, laminin, VEGF and CTGF in CCl(4)-treated rats.
COX-2 is involved in the fibrogenesis of livers and the formation of portal hypertension in CCl(4)-treated rats. Selective inhibition of COX-2 by rofecoxib reduces portal hypertension and this is associated with antifibrotic activity as well as a reduction of COX-2-derived vasoactive substance.
环氧化酶-2（COX-2）是一种诱导性酶，积极参与炎症和伤口愈合过程，在肝硬化肝脏中发现其表达上调。本研究旨在探讨选择性抑制COX-2对大鼠肝硬化和门静脉高压发展的影响。
用四氯化碳（CCl₄）诱导Sprague-Dawley大鼠肝硬化。将罗非昔布（一种高度选择性COX-2抑制剂）以10 mg/kg/天的剂量口服给予大鼠。在给予CCl₄后8周，采用导管插入法测量门静脉压力，随后采集肝脏样本。用苏木精和伊红以及Masson三色染色法分析肝脏组织病理学。分别用免疫组织化学染色和蛋白质印迹法检测肝脏中活化的α平滑肌肌动蛋白（α-SMA）阳性肝星状细胞（HSC）以及I、III、IV型胶原蛋白、层粘连蛋白的蛋白质水平，以及两种纤维化介质血管内皮生长因子（VEGF）和结缔组织生长因子（CTGF）。用酶免疫测定法测量肝脏中血栓素B₂（TXB₂）的水平，TXB₂是一种源自COX的强效血管收缩物质。
口服罗非昔布可降低经CCl₄处理8周的大鼠的门静脉压力。这与大鼠肝脏中胶原蛋白积累和TXB₂水平的显著降低有关。此外，发现给予罗非昔布可减少CCl₄处理大鼠中活化HSC的数量，并下调三种检测到的胶原蛋白、层粘连蛋白、VEGF和CTGF的肝脏蛋白质水平。
COX-2参与CCl₄处理大鼠肝脏的纤维化形成和门静脉高压的形成。罗非昔布对COX-2的选择性抑制可降低门静脉高压，这与抗纤维化活性以及COX-2衍生的血管活性物质的减少有关。
