Experimental study of tissue transglutaminase inhibitor on the progression of liver fibrosis.

Abstract

Objective To observe the effects of cystamine, a tissue transglutaminase (tTG) inhibitor, on the development of rat liver fibrosis induced by carbon tetrachloride. Methods One hundred male SD rats were randomly divided into control group (n=20), hepatic fibrosis group (n=40) and cystamine group (n=40) . Liver fibrosis model was induced by intraperitoneal injection of carbon tetrachloride. Cystamine (112 mg·kg-1·d-1) was administered by intraperitoneal injection 2 days before injection of carbon tetrachloride. The rats were sacrificed at weeks 4 and 8, and the liver tissues and serum specimens were obtained. The mRNA expression of tTG, smooth muscle-alpha (α-SMA), collagen-Ⅰ and tissue inhibitors of metalloproteinase-1 (TIMP-1) were detected by real time PCR. The protein expression of tTG and α-SMA, liver function and content of hydroxyproline in liver tissues were determined by Western blot. Histological changes of the liver was observed under microscope. The fibrosis conditions of rat liver in each group were evaluated according to the semi-quantita-tive scoring system. All the data were analyzed by one-way ANOVA. Results Eight weeks after the injection of carbon tetrachloride, obvious injury of the liver in liver fibrosis group was observed. The levels of alanine trans-aminase (ALT), total bile acid, total bilirubin, hydroxyproline, tTG, α-SMA, collagen-Ⅰ and TIMP-1 were (1313±157)U/L, (99.9±18.5)μmol/L, (10.9±1.6)μmoL/L, (55±12)μg/g, 145.6±51.2, 130.3±44.6, 211.3±75.1 and 162.4±53.5. After administration of cystamine, the levels of ALT, total bile acid, total bilirubin, hydroxyproline, tTG, α-SMA, collagen-Ⅰ and TIMP-1 were (378±87) U/L, (61.0±12.7) μmol/L, (9.8±1.7) μmol/L, (70±14 ) μg/g, 48.6±12.3, 40.7±12.3, 63.9±16.0, 59.2μ23.4. Conclusion Cystamine can alleviate the carbon tetrachloride-induced rat liver fibrosis by inhibiting the tTG pathway. Key words: Tissue transglutaminase; Hepatic stellate cell; Extracellular matrix; Liver fibrosis