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Gene Transfer of c-met Confers Protection Against d-Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

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Abstract

Background

Acute liver failure (ALF) is characterized by impaired regeneration of hepatocytes, partially resulting from the defective signaling between elevated levels of hepatocyte growth factor (HGF) and the downregulation of its receptor, c-met.

Aims

In this study, we assess the therapeutic efficacy of in vivo c-met gene transfer in ALF.

Methods

We established a d-galactosamine/lipopolysaccharide (d-GalN/LPS)-induced ALF model in rats. The levels of HGF and c-met in d-GalN/LPS rats were compared with vehicle-injected rats and those undergoing liver regeneration following partial hepatectomy (PH). To deliver c-met in vivo, pcDNA-c-met was constructed and transfected into the rat liver via hydrodynamic injection. Control rats were transfected with the pcDNA3.1 plasmid. The expressions of c-met in different tissues were examined by immunohistochemistry. Hepatocyte proliferation and apoptosis were determined by PCNA staining and TUNEL assay, respectively. The survival of rats in the control and c-met-expressing rats was compared by Kaplan–Meier analysis.

Results

Compared with control rats, d-GalN/LPS or PH -treated rats had significantly higher levels of HGF (P < 0.01). d-GalN/LPS also led to significantly lower c-met expression in the liver (P < 0.01) than PH. The in vivo c-met gene transfer led to its specific expression on hepatocytes, which was accompanied by the enhancement of hepatocyte proliferation, a reduction in apoptosis, as well as significant improvement in overall survival (P < 0.01).

Conclusions

This study provides the initial evidence that c-met may serve as a novel target for gene therapy, and may be of clinical benefit in the treatment of patients with ALF.

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Acknowledgments

We thank Medjaden Bioscience Limited for assisting in the preparation of this manuscript. This study was supported by the grants from the National Natural Science Foundation of China (NSFC, No. 30800973) and the Science and Technological Fund of Anhui Province for Outstanding Youth (No.10040606Y14).

Conflict of interest

The authors declare that they have no competing of interests.

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Authors and Affiliations

  1. Department of Infectious Diseases, Affiliated Provincial Hospital, Anhui Medical University, Hefei, 230001, China

    Chuanlong Zhu, Wenting Li & Rentao Gao

  2. Department of Pediatrics, Affiliated Provincial Hospital, Anhui Medical University, Hefei, 230001, China

    Yuwen Li

  3. Department of Central Lab, Affiliated Provincial Hospital, Anhui Medical University, Hefei, 230001, China

    Quan Wu

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  1. Chuanlong Zhu
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  2. Yuwen Li
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Correspondence to Chuanlong Zhu.

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Zhu, C., Li, Y., Li, W. et al. Gene Transfer of c-met Confers Protection Against d-Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure. Dig Dis Sci 57, 925–934 (2012). https://doi.org/10.1007/s10620-012-2052-4

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  • DOI: https://doi.org/10.1007/s10620-012-2052-4

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