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Viral gene delivery of superoxide dismutase attenuates experimental cholestasis-induced liver fibrosis in the rat

Gene Therapy volume 9, pages 183–191 (2002)Cite this article

Abstract

Hydrophobic bile acids lead to generation of oxygen free radicals in mitochondria. Accordingly, this study investigated if gene delivery of superoxide dismutase (SOD) would reduce hepatic injury caused by experimental cholestasis. Rats were given adenovirus (Ad; 3 × 109 p.f.u., i.v.) carrying the bacterial control gene lacZ, mitochondrial Mn-SOD or cytosolic Cu/Zn-SOD genes 3 days before bile duct ligation. Both Mn- and Cu/Zn-SOD activity was increased in the liver about four-fold 3 days after viral infection. Serum alanine transaminase increased to about 710 U/l after bile duct ligation, which was blunted by about 70% in rats receiving Ad-Mn-SOD, but by only 30% in rats receiving Ad-Cu/Zn-SOD. Bile duct ligation caused focal necrosis, apoptosis and fibrosis in the liver and increased collagen α1 mRNA about 20-fold. These effects were reduced significantly by Ad-Mn-SOD, but not by Ad-Cu/Zn-SOD. In addition, bile duct ligation increased 4-hydroxynonenal, a product of lipid peroxidation, activated NF-κB and increased synthesis of TNFα and TGF-β. These effects were also blunted significantly by Ad-Mn-SOD, but not by Ad-Cu/Zn-SOD. Taken together, it is concluded that cholestasis causes liver injury by mechanisms involving mitochondrial oxidative stress. Gene delivery of mitochondrial Mn-SOD blocks formation of oxygen radicals and production of toxic cytokines thereby minimizing liver injury caused by cholestasis.

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Acknowledgements

This work was supported, in part, by grants from NIH. The authors thank Mr Bob Schoonhoven for his assistance in immunohistochemical staining for β-galactosidase.

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Authors and Affiliations

  1. Department of Pharmacology, University of North Carolina at Chapel Hill, NC, USA

    Z Zhong, M Froh, MD Wheeler, O Smutney, TG Lehmann & RG Thurman

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Zhong, Z., Froh, M., Wheeler, M. et al. Viral gene delivery of superoxide dismutase attenuates experimental cholestasis-induced liver fibrosis in the rat. Gene Ther 9, 183–191 (2002). https://doi.org/10.1038/sj.gt.3301638

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