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Liver-specific Fas silencing prevents galactosamine/lipopolysaccharide-induced liver injury

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Abstract

Acute liver failure (ALF) is a life threatening disease for which only few treatment options exist. The molecular pathways of disease progression are not well defined, but the death receptor Fas (CD95/Apo-1) appears to play a pivotal role in hepatocyte cell death and the development of ALF. Here, we explored posttranscriptional gene silencing of Fas by RNAi to inhibit pathophysiological gene expression. For targeting Fas expression in mice, Fas siRNA was formulated with the liver-specific siRNA delivery system DBTC. Treatment of mice with DBTC/siRNAFas reduced Fas expression in the liver, but not in the spleen, lung, kidney or heart. Furthermore, silencing of Fas receptor was effective in blocking or reducing several aspects of ALF when it was tested in mice exposed to galactosamine/lipopolysaccharide (G/L), a well-known model of ALF. The application of DBTC/siRNAFas 48 h prior G/L exposure resulted in amelioration of hepatic perfusion, reduction of hepatocellular death and increase of survival rate. The administration of DBTC/siRNAFas formulation further diminished the inflammatory response upon G/L challenge, as indicated by a marked decrease of TNFα mRNA expression. However, IL-6 plasma concentration remained unaffectedly by DBTC/siRNAFas formulation. Since the specific silencing of hepatic Fas expression only partially protected from inflammation, but completely attenuated apoptotic and necrotic cell death as well as microcirculatory dysfunction, the development of therapeutic strategies with DBTC lipoplex formulations to treat ALF should be combined with anti-inflammatory strategies to reach maximal therapeutic efficacy.

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Acknowledgments

The authors cordially thank Berit Blendow, Dorothea Frenz, Maren Nerowski, and Eva Lorbeer-Rehfeldt (Institute for Experimental Surgery, University of Rostock, Germany) for excellent technical assistance.

Conflict of interest

Volker Fehring, Ute Schaeper, and Ulf Schulze-Topphoff are employees of and have stock options from Silence Therapeutics plc and declare competing financial interest. The other authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute for Experimental Surgery, Rostock University Medical Center, University of Rostock, Schillingallee 69a, 18057, Rostock, Germany

    Angela Kuhla, Michael Thrum, Kerstin Abshagen & Brigitte Vollmar

  2. Silence Therapeutics GmbH, Berlin, Germany

    Ute Schaeper, Volker Fehring & Ulf Schulze-Topphoff

Authors
  1. Angela Kuhla
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  2. Michael Thrum
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  3. Ute Schaeper
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  4. Volker Fehring
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  5. Ulf Schulze-Topphoff
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  6. Kerstin Abshagen
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  7. Brigitte Vollmar
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Corresponding author

Correspondence to Angela Kuhla.

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Kuhla, A., Thrum, M., Schaeper, U. et al. Liver-specific Fas silencing prevents galactosamine/lipopolysaccharide-induced liver injury. Apoptosis 20, 500–511 (2015). https://doi.org/10.1007/s10495-015-1088-2

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  • DOI: https://doi.org/10.1007/s10495-015-1088-2

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