Yonsei Med J.  2015 Nov;56(6):1572-1581. 10.3349/ymj.2015.56.6.1572.

Thalidomide Accelerates the Degradation of Extracellular Matrix in Rat Hepatic Cirrhosis via Down-Regulation of Transforming Growth Factor-beta1

• Lv P
• Meng Q
• Liu J
• Wang C

• KMID: 2345885
• DOI: http://doi.org/10.3349/ymj.2015.56.6.1572

Abstract

PURPOSE
The degradation of the extracellular matrix has been shown to play an important role in the treatment of hepatic cirrhosis. In this study, the effect of thalidomide on the degradation of extracellular matrix was evaluated in a rat model of hepatic cirrhosis.
MATERIALS AND METHODS
Cirrhosis was induced in Wistar rats by intraperitoneal injection of carbon tetrachloride (CCl4) three times weekly for 8 weeks. Then CCl4 was discontinued and thalidomide (100 mg/kg) or its vehicle was administered daily by gavage for 6 weeks. Serum hyaluronic acid, laminin, procollagen type III, and collagen type IV were examined by using a radioimmunoassay. Matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and alpha-smooth muscle actin (alpha-SMA) protein in the liver, transforming growth factor beta1 (TGF-beta1) protein in cytoplasm by using immunohistochemistry and Western blot analysis, and MMP-13, TIMP-1, and TGF-beta1 mRNA levels in the liver were studied using reverse transcriptase polymerase chain reaction.
RESULTS
Liver histopathology was significantly better in rats given thalidomide than in the untreated model group. The levels of TIMP-1 and TGF-beta1 mRNA and protein expressions were decreased significantly and MMP-13 mRNA and protein in the liver were significantly elevated in the thalidomide-treated group.
CONCLUSION
Thalidomide may exert its effects on the regulation of MMP-13 and TIMP-1 via inhibition of the TGF-beta1 signaling pathway, which enhances the degradation of extracellular matrix and accelerates the regression of hepatic cirrhosis in rats.

Keyword

Thalidomide; cirrhosis; extracellular matrix; matrix metalloproteinase-13; tissue inhibitor of metalloproteinase-1; transforming growth factor-beta1

MeSH Terms

Actins
Animals
Carbon Tetrachloride/toxicity
Collagen Type III/metabolism
Down-Regulation
Extracellular Matrix/metabolism
Immunohistochemistry
Immunosuppressive Agents/*pharmacology
Liver Cirrhosis, Experimental/chemically induced/*metabolism/pathology/*prevention & control
Male
RNA, Messenger/analysis/metabolism
Rats
Rats, Wistar
Thalidomide/*pharmacology
Tissue Inhibitor of Metalloproteinase-1/biosynthesis/*drug effects
Transcription Factor RelA/biosynthesis/drug effects
Transforming Growth Factor beta1/biosynthesis/*drug effects
Transforming Growth Factors/metabolism
Actins
Carbon Tetrachloride
Collagen Type III
Immunosuppressive Agents
RNA, Messenger
Thalidomide
Tissue Inhibitor of Metalloproteinase-1
Transcription Factor RelA
Transforming Growth Factor beta1
Transforming Growth Factors