Yuan Guang-Jin, Zhang Ming-Liang, Gong Zuo-Jiong
Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China.
World J Gastroenterol. 2004 Apr 1;10(7):1047-51. doi: 10.3748/wjg.v10.i7.1047.
To investigate effects of pioglitazone on rat hepatic fibrosis and to explore its mechanism.
Rat hepatic fibrosis was induced by carbon tetrachloride (CCl(4)). Forty Sprague-Dawley rats were divided randomly into 4 groups: control, model, and two treatment (PI, PII) groups. Except for rats in control group, all rats were given subcutaneous injection of 400 mL/L CCl(4), twice a wk for 8 wk. Rats in PI and PII groups were also treated with pioglitazone of 3 mg/kg, daily via gastrogavage beginning on the 1(st) day and at the end of the 2(nd) week, administration of CCl(4) respectively. Liver functions (ALT, AST), serum fibrotic markers (HA, LN, PCIII) and hepatic hydroxyproline (HP) concentration were determined respectively. Histochemical staining of formalin-fixed liver sections with HE, Masson-Trichrome, and immunohistochemical staining for alpha-smooth muscle actin (alpha-SMA) were performed. Modified Knodell and Chevallier semi-quantitative scoring system (SSS) was used to evaluate necroinflammatory activity and fibrosis degree.
Compared with model group, pioglitazone significantly reduced the serum levels of ALT, AST, HA, LN and PCIII (P<0.05 or <0.01). The HP concentrations in PI (210.90+/-24.07 microg/g), and PII (257.36+/-30.55 microg/g) groups were also lower than those in model group (317.80+/-36.44 microg/g) (P<0.01). Histologic examination showed that PI and PII groups had milder hepatocellular degeneration, necrosis and infiltration of inflammatory cells, and thinner or less fibrotic septa than did model group. The scores for necroinflammation in PI (2.80+/-1.03), and PII (3.00+/-1.05) groups were significantly reduced as compared with model group (4.88+/-2.30) (P<0.05 or <0.01); the fibrosis scores in PI (3.40+/-1.65), and PII (4.60+/-1.35) groups were also markedly lower than those in model group (7.00+/-3.21) (P<0.05 or <0.01). Immunohistochemical staining showed that expression of alpha-SMA in PI and PII groups was ameliorated dramatically compared with model group.
PPARgamma agonist pioglitazone greatly retards the progression of rat hepatic fibrosis induced by CCl(4) through inhibition of HSC activation and amelioration of hepatocyte necroinflammation in rats.
研究吡格列酮对大鼠肝纤维化的影响并探讨其作用机制。
采用四氯化碳（CCl₄）诱导大鼠肝纤维化。将40只Sprague-Dawley大鼠随机分为4组：对照组、模型组和两个治疗组（PI组、PII组）。除对照组大鼠外，其余大鼠皮下注射400 mL/L CCl₄，每周2次，共8周。PI组和PII组大鼠从第1天开始每天经胃管给予3 mg/kg吡格列酮，分别在第2周结束时给予CCl₄。分别测定肝功能（ALT、AST）、血清纤维化标志物（HA、LN、PCIII）和肝羟脯氨酸（HP）浓度。对福尔马林固定的肝组织切片进行HE、Masson三色染色及α-平滑肌肌动蛋白（α-SMA）免疫组化染色。采用改良的Knodell和Chevallier半定量评分系统（SSS）评估坏死炎症活动度和纤维化程度。
与模型组相比，吡格列酮显著降低了血清ALT、AST、HA、LN和PCIII水平（P<0.05或<0.01）。PI组（210.90±24.07 μg/g）和PII组（257.36±30.55 μg/g）的HP浓度也低于模型组（317.80±36.44 μg/g）（P<0.01）。组织学检查显示，PI组和PII组肝细胞变性、坏死及炎性细胞浸润较模型组轻，纤维化间隔更薄或更少。PI组（2.80±1.03）和PII组（3.00±1.05）的坏死炎症评分与模型组（4.88±2.30）相比显著降低（P<0.05或<0.01）；PI组（3.40±1.65）和PII组（4.60±1.35）的纤维化评分也明显低于模型组（7.00±3.21）（P<0.05或<0.01）。免疫组化染色显示，与模型组相比，PI组和PII组α-SMA的表达明显改善。
PPARγ激动剂吡格列酮通过抑制大鼠肝星状细胞激活和改善肝细胞坏死炎症，大大延缓了CCl₄诱导的大鼠肝纤维化进程。
