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Dynamic change of MMP-1/TIMP-1 expression in experimental immune hepatic fibrosis
Zhi-Jun Duan, Xiang Hu, Zhi-Hong Gao, Chen Tan, Hong Yuan, Shi-Jun Li
Zhi-Jun Duan, Zhi-Hong Gao, Chen Tan, Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
Xiang Hu, Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
Hong Yuan, Shi-Jun Li, Testing Center, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
Correspondence to: Zhi-Jun Duan, Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China. email@example.com
Received: February 28, 2005 Revised: March 11, 2005 Accepted: March 22, 2005 Published online: May 1, 2005
AIM: To evaluate the roles of matrix metalloproteinase-1/ tissue inhibitor of metalloproteinse-1 (MMP-1/TIMP-1) in the course of formation and progression of liver fibrosis.
METHODS: Forty-eight female SD rats, 120-150 g in weight, were divided randomly into 2 groups, 8 rats in normal control group and 40 rats in fibrosis group. The fibrotic animal model was established according to the method of Blackwell with some modifications. Human serum albumin (HSA)-sensitized rats were further attacked by i. v. injection of HSA through the coccygeal vein. Liver tissues were obtained 0, 2, 4, 6, and 8 weeks after the attack. Liver hydroxyproline (HYP) content was determined, and HE, argentophilic as well as Van Gieson's (VG) stainings were performed to monitor the process of fibroproliferation. The protein and RNA of MMP-1/TIMP-1 were analyzed using ELISA and semi-quantitative RT-PCR, respectively.
RESULTS: Gradual formation of hepatic fibrosis was detected in the rats, which indicated an ideal model to study the process of generation and development of fibrosis. MMP-1 protein was present in the normal liver, with no significant change in fibrosis and cirrhosis (P>0.05). In contrast, TIMP-1 protein was increased progressively (P<0.01, after 4 weeks), reaching the peak in the stage of cirrhosis (the value after 8 wks was increased by 4 folds). In consistence with the changes of the proteins, MMP-1 mRNA expression did not alter significantly during the fibrosis process (P>0.05), while TIMP-1 mRNA expression was increased gradually (P<0.01, after 4 weeks). MMP-1/TIMP-1 ratio tended to decrease in this process. The change was more profound after 4 weeks (P<0.01). Moreover, the extent of the increase of TIMP-1 and the decrease of MMP-1/TIMP-1 ratio was well correlated with the extent of fibrosis, as revealed by the study of rats in different groups with different grades of fibroproliferation.
CONCLUSION: The main cause responsible for the deposition of extracellular matrix (ECM) during fibrosis might not be a gradual decrease in MMP-1 level, but a progressing increase in TIMP-1 level, which suppresses the activity of MMP-1 so as to diminish matrix degradation. A gradual decrease of MMP-1/TIMP-1 ratio during this process indicates a progressing disproportion between MMP-1 and TIMP-1, which accelerates the fibrosis process. TIMP-1 expression and MMP-1/TIMP-1 ratio are two useful indexes to reflect the fibrotic extent.
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