Abstract
Acute liver failure is a devastating illness of various causes with considerable mortality. Hepatic stimulator substance (HSS) has been suggested for use as a protective agent against acute hepatic injury induced by chemical poisons because it has a variety of biological activities. However, the mechanism whereby HSS protects against hepatotoxins is poorly understood. In this study, we established a hepatic gene transfer system via hydrodynamic tail vein injection to deliver a naked plasmid containing the human HSS gene (hHSS) and analyzed HSS-mediated protection of the liver during fulminant hepatic failure (FHF) induced by d-galactosamine (d-gal) and lipopolysaccharide (LPS). The results showed that the reporter gene, enhanced green fluorescent protein, was efficiently expressed in the liver of BALB/c mice. Hydrodynamic-based transfection of hHSS yielded a 70% survival rate compared with 36.7% for the control group at 24 h after d-gal/LPS treatment. In addition, hHSS expression preserved liver morphology and function. It is noteworthy that hHSS hydrodynamic-based transfer ameliorated indices of the mitochondrial permeability transition (MPT) resulting from the toxic effects of d-gal/LPS on the liver such as mitochondrial swelling, mitochondrial transmembrane potential disruption, and cytochrome c translocation. Furthermore, mitochondrial morphology and ATP levels were maintained in hHSS-administered mice. HSS-mediated protection was similar to that observed with the MPT inhibitor N-methyl-4-isoleucine-cyclosporin (NIM811), indicating a possible role for HSS in the regulation of MPT. In conclusion, a single dose of hHSS plasmid protected mice from FHF, and this hepatoprotective effect seemed to correlate with the inhibition of MPT.
Footnotes
This work was supported by the National Key Basic Project [Grant 2010CB5344903] and the National Natural Science Foundation of China [Grant 81070352].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.181305.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- HSS
- hepatic stimulator substance
- hHSS
- human HSS
- ALT
- alanine aminotransferase
- ALR
- augmenter of liver regeneration
- AST
- aspartate aminotransferase
- CsA
- cyclosporin A
- d-gal
- d-galactosamine
- GFP
- green fluorescent protein
- EGFP
- enhanced GFP
- FHF
- fulminant hepatic failure
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- HTV
- hydrodynamic tail vein
- LDH
- lactate dehydrogenase
- LPS
- lipopolysaccharide
- JC-1
- 5,5,6,6-tetrachloro-1,1,3,3-tetraethylbenzimidazolocarbocyanine iodide
- MPT
- mitochondrial permeability transition
- MTP
- mitochondrial transmembrane potential
- NIM811
- N-methyl-4-isoleucine-cyclosporin
- pCMV
- cytomegalovirus promoter
- VDAC
- voltage-dependent anion channel.
- Received March 8, 2011.
- Accepted May 24, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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