Cystamine ameliorates liver fibrosis induced by carbon tetrachloride via inhibition of tissue transglutaminase.
OBJECTIVE
To investigate the anti-fibrosis effect of the tissue transglutaminase (tTG) specific inhibitor cystamine on liver fibrosis.


METHODS
Sixty-eight male Sprague Dawley rats were divided into three groups: normal control, liver fibrosis control and cystamine-treated group. Liver fibrosis was induced by intraperitoneal injection of carbon tetrachloride (CCl(4)), and Cystamine was administrated by intraperitoneal injection starting 2 d before the first administration of CCl(4). Animals in each group were further divided into 2 subgroups according to two time points of 4 wk and 8 wk after treatment. Hepatic function, pathological evaluation (semi-quantitative scoring system, SSS) and liver hydroxyproline (Hyp) content were examined. Real-time PCR was used to detect the expression of tTG, smooth muscle alpha actin (alpha-SMA), tissue inhibitor of metalloproteinase 1 (TIMP-1) and collagen-1 mRNA. The expressions of tTG and alpha-SMA protein were detected by Western Blotting.


RESULTS
Eight weeks after treatment, the SSS score of liver was significantly less in the cystamine group than that in the fibrosis control group (P < 0.01). The levels of alanine aminotransferase (ALT) and total bile acid (TBA) at the 4 wk and 8 wk time points were decreased in the cystamine group compared with those in fibrosis controls (P < 0.01). Liver hydroxyproline content at the 4 wk and 8 wk time points showed a substantial reduction in the cystamine group compared to fibrosis controls (P < 0.01). The expression of tTG, alpha-SMA, collagen-1, TIMP-1 mRNA and tTG, as well as alpha-SMA protein was downregulated in the cystamine group compared to fibrosis controls.


CONCLUSIONS
Cystamine can ameliorate CCl(4) induced liver fibrosis and protect hepatic function. The possible mechanism is related to the reduced synthesis of the extracellular matrix (ECM) caused by the inhibition of hepatic stellate cell activation and decreased expression of TIMP-1.
Qiu
Jiang-Feng
JF
Department of General Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
Zhang
Zhi-Qi
ZQ
Chen
Wei
W
Wu
Zhi-Yong
ZY
D000199:Actins / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride; D003094:Collagen / Q000378:metabolism; D003538:Cystamine / Q000627:therapeutic use*; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006909:Hydroxyproline / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000199:Actins; D002251:Carbon Tetrachloride; D003094:Collagen; D003538:Cystamine; D004791:Enzyme Inhibitors; D006909:Hydroxyproline; D019715:Tissue Inhibitor of Metalloproteinase-1; D011503:Transglutaminases; C498862:Acta2 protein, rat
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