Effects of PPARg agonist pioglitazone on rat hepatic fibrosis.
OBJECTIVE
To investigate effects of pioglitazone on rat hepatic fibrosis and to explore its mechanism.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Yuan
Guang-Jin
GJ
Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China. guangjin_yuan@hotmail.com
Zhang
Ming-Liang
ML
Gong
Zuo-Jiong
ZJ
D000818:Animals; D006909:Hydroxyproline / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000819:agonists*
D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D006909:Hydroxyproline; D000077205:Pioglitazone