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Inhibitory effect of antisense oligonucleotide targeting TIMP-2 on immune-induced liver fibrosis.

AbstractINTRODUCTION:
We previously reported that both experimental and human studies have shown the importance of TIMP-1 and TIMP-2 in the development of liver fibrosis, a disease mostly caused by HBV and HCV infection in China. Inhibiting the expression of TIMP-1 by an antisense oligonucleotide (ASON) can prevent liver fibrosis through decreasing the deposition of collagen I and III. Whether blocking the expression of TIMP-2 has the same effect on liver fibrosis is not clear.
MATERIALS AND METHODS:
To interfere with this potentially effective target, we designed and synthesized two different ASON targeting TIMP-2, then mixed and transfected them by hydrodynamic injection into the rat livers with immune-induced liver fibrosis. We isolated HSCs from the HSA-induced rat model with liver fibrosis, and transfected them with ASON or sense oligonucleotide in vitro.
RESULTS:
We observed that TIMP-2 ASON markedly reduced the expression of TIMP-2 by real-time PCR, Western blot, and enzyme linked immunosorbent assay. However, TIMP-2 ASON had little effect on alpha-SMA expression in vitro by Western blot. Inhibition of the expression of TIMP-2 by TIMP-2 ASON clearly decreased deposition of collagen I and IV, ameliorated liver pathology, and improved the liver function among the rats with immune-induced liver fibrosis.
CONCLUSION:
The results suggested that TIMP-2 ASON could prevent the progression of liver fibrosis in this rat model. It is possible that this could form the basis for exploration of new liver anti-fibrosis drugs at a genetic level.
AuthorsQing-He Nie, Chuan-Long Zhu, Ya-Fei Zhang, Jie Yang, Jiu-Cong Zhang, Ren-Tao Gao
JournalDigestive diseases and sciences (Dig Dis Sci) Vol. 55 Issue 5 Pg. 1286-95 (May 2010) ISSN: 1573-2568 [Electronic] United States
PMID19517234 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Oligonucleotides, Antisense
  • Serum Albumin
  • Tissue Inhibitor of Metalloproteinase-2
  • Collagen
Topics
  • Animals
  • Blotting, Western
  • Chromatography, High Pressure Liquid
  • Collagen (metabolism)
  • Disease Progression
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Genetic Therapy (methods)
  • Liver Cirrhosis (immunology, prevention & control)
  • Oligonucleotides, Antisense (genetics, pharmacology)
  • Random Allocation
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serum Albumin
  • Statistics, Nonparametric
  • Tissue Inhibitor of Metalloproteinase-2 (genetics)

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