Differential Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Thioacetamide-Induced Chronic Liver Injury

Hepatic fibrogenesis, a complex process that involves a marked accumulation of extracellular matrix components, activation of cells capable of producing matrix materials, cytokine release, and tissue remodeling, is regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). The MMP-TIMP balance can regulate liver fibrogenesis. The aim of this study was to evaluate the expression patterns of MMPs and TIMPs during thioacetamide (TAA)-induced liver fibrogenesis. Chronic liver injury was induced with TAA (200 mg/kg i. p.) for 4 or 7 weeks in male Sprague-Dawley rats. Hepatic injury and fibrosis were assessed by hematoxylin-eosin (H&E) staining, and collagen deposition was confirmed by Sirius Red staining. The level of hepatic injury was quantified by serological analysis. The transcriptional and translational levels of alpha-smooth muscle actin (alpha-SMA), MMPs, and TIMPs in the liver were measured by Western blotting, RT-PCR, and immunohistochemistry. MMP, TIMP, and alpha-SMA were observed along fibrotic septa and portal spaces around the lobules. TAA treatment increased transcription of both MMPs and TIMPs, but only TIMPs showed increased translation. The dominant expression of TIMPs may regulate the function of MMPs to maintain liver fibrosis induced by TAA.This study was supported by a grant (No. 04-2006-0990) from the Seoul National University Hospital of Korea.Cheong JY, 2008, J KOREAN MED SCI, V23, P61, DOI 10.3346/jkms.2008.23.1.61Taras D, 2007, J HEPATOL, V46, P69, DOI 10.1016/j.jhep.2006.06.015Uchinami H, 2006, HEPATOLOGY, V44, P420, DOI 10.1002/hep.21268Wang CH, 2006, GENE THER, V13, P1000, DOI 10.1038/sj.gt.3302744Waters NJ, 2005, CHEM RES TOXICOL, V18, P639, DOI 10.1021/tx049869bLindquist JN, 2004, J BIOL CHEM, V279, P23822, DOI 10.1074/jbc.M314060200Nie QH, 2004, WORLD J GASTROENTERO, V10, P86Iredale JP, 2003, BRIT MED J, V327, P143Benyon RC, 2001, SEMIN LIVER DIS, V21, P373Kim TH, 2000, HEPATOLOGY, V31, P75Yong VW, 1998, TRENDS NEUROSCI, V21, P75Butler GS, 1998, J BIOL CHEM, V273, P871Takahara T, 1997, HEPATOLOGY, V26, P1521Herbst H, 1997, AM J PATHOL, V150, P1647Krane SM, 1996, J BIOL CHEM, V271, P28509Sato H, 1996, FEBS LETT, V393, P101Knauper V, 1996, J BIOL CHEM, V271, P17124STRONGIN AY, 1995, J BIOL CHEM, V270, P5331MILANI S, 1994, AM J PATHOL, V144, P528IREDALE JP, 1992, J CLIN INVEST, V90, P282SCHEUER PJ, 1991, J HEPATOL, V13, P372TSUKAMOTO H, 1990, SEMIN LIVER DIS, V10, P56LIOTTA LA, 1990, SEMIN CANCER BIOL, V1, P99