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Inhibitory Effect of Antisense Oligonucleotide Targeting TIMP-2 on Immune-Induced Liver Fibrosis

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Abstract

Introduction

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 α-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.

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Acknowledgments

This work was supported a grant from the Science and Technology Foundation of Shaanxi Province (no. 2003K10G63) and the Science and Technology Foundation of Anhui Province (no. 07010302195).

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Authors and Affiliations

  1. Chinese PLA Centre of Diagnosis and Treatment for Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, 710038, Xi’an, Shaanxi Province, People’s Republic of China

    Qing-He Nie, Jie Yang & Jiu-Cong Zhang

  2. Department of Infectious Disease, Affiliated Provincial Hospital of Anhui Medical University, 230001, Hefei, Anhui Province, People’s Republic of China

    Chuan-Long Zhu & Ren-Tao Gao

  3. Institute of Digestive Diseases of PLA and State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, 710032, Xi’an, Shaanxi Province, People’s Republic of China

    Ya-Fei Zhang

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  1. Qing-He Nie
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Correspondence to Qing-He Nie.

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Nie, QH., Zhu, CL., Zhang, YF. et al. Inhibitory Effect of Antisense Oligonucleotide Targeting TIMP-2 on Immune-Induced Liver Fibrosis. Dig Dis Sci 55, 1286–1295 (2010). https://doi.org/10.1007/s10620-009-0858-5

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