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Alpha-1-antitrypsin inhibits acute liver failure in mice

Authors

  • Nils Jedicke,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. Chronic Infection and Cancer Group, Helmholtz Center for Infection Research, Braunschweig, Germany
    3. Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University Hospital Tuebingen, Tübingen, Germany
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  • Nina Struever,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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  • Nupur Aggrawal,

    1. Department of Respiratory Medicine, Hannover Medical School, Hanover, Germany
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  • Tobias Welte,

    1. Department of Respiratory Medicine, Hannover Medical School, Hanover, Germany
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  • Michael P. Manns,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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  • Nisar P. Malek,

    1. Department of Internal Medicine I, University Hospital Tuebingen, Tübingen, Germany
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  • Lars Zender,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. Chronic Infection and Cancer Group, Helmholtz Center for Infection Research, Braunschweig, Germany
    3. Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University Hospital Tuebingen, Tübingen, Germany
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  • Sabina Janciauskiene,

    Corresponding author
    1. Department of Respiratory Medicine, Hannover Medical School, Hanover, Germany
    • Address reprint requests to: T. Wuestefeld, Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University Hospital Tuebingen, Ottfried-Mueller-Strasse 10, 72076 Tuebingen, Germany. E-mail: Torsten.Wuestefeld@med.uni-tuebingen.de or S. Janciauskiene, Department of Respiratory Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hanover, Germany. E-mail: janciauskiene.sabina@mh-hanover.de

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    • These authors contributed equally to this work.

  • Torsten Wuestefeld

    Corresponding author
    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. Chronic Infection and Cancer Group, Helmholtz Center for Infection Research, Braunschweig, Germany
    3. Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University Hospital Tuebingen, Tübingen, Germany
    • Address reprint requests to: T. Wuestefeld, Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University Hospital Tuebingen, Ottfried-Mueller-Strasse 10, 72076 Tuebingen, Germany. E-mail: Torsten.Wuestefeld@med.uni-tuebingen.de or S. Janciauskiene, Department of Respiratory Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hanover, Germany. E-mail: janciauskiene.sabina@mh-hanover.de

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    • These authors contributed equally to this work.


  • Potential conflict of interest: Dr. Janciauskiene received grants from Grifols and Baxter. She has intellectual property rights with Grifols.

  • Supported by the German Research Foundation, DFG [(Emmy Noether Programme ZE 545/2-1 to L.Z.), “REBIRTH” cluster of Excellence, project “Liver regeneration”, SFB/TRR77, project B4) to L.Z.], the European Commission (project “HEPTROMIC”), the Wilhelm Sander Stiftung (2009.005.2 to L.Z.), the Bear Necessities Pediatric Cancer Foundation and the Federal German Ministry for Education and Research (BMBF) (ARCHES AWARD to L.Z.). N. Jedicke was supported by Hannover Biomedical Research School StrucMed Programme and SFB TRR77 German Liver Cancer Stipend; S. Janciauskiene was supported by Deutsche Forschungsgemeinschaft (SFB 587, A18) and Deutsches Zentrum für Lungenforschung (DZL).

Abstract

Acute liver failure remains a critical clinical condition, with high mortality rates, and increased apoptosis of hepatocytes represents a key event in the cause of liver failure. Alpha-1-antitrypsin (AAT) is synthesized and secreted mainly by hepatocytes, and plasma purified AAT is used for augmentation therapy in patients with AAT deficiency. Because AAT therapy exerts antiinflammatory and immune modulatory activities in various experimental models, and it was recently suggested that AAT exerts antiapoptotic activities, we aimed to explore whether administration of AAT may represent a therapeutic strategy to treat acute liver failure in mice. Well-established preclinical models of acute liver failure such as the Jo2 FAS/CD95 activating model and models of acetaminophen and α-amanitin poisoning were used. Therapeutic effects of AAT were evaluated by monitoring animal survival, histopathological changes, measurement of caspase activity, and serum cytokine levels. Systemic treatment with AAT significantly decreased Jo2-induced liver cell apoptosis and prolonged survival of mice. Native and oxidized (lacking elastase inhibitory activity) forms of AAT were equally effective in preventing acute liver injury and showed direct inhibition of active caspase-3 and −8 in liver homogenates and in a cell-free system in vitro. Concomitantly, mice treated with AAT showed significantly lower serum levels of tumor necrosis factor alpha (TNF-α), which also paralleled the reduced activity of ADAM17 (TACE). Noticeably, the increased survival and a reduction of apoptotic hepatocytes were also observed in the α-amanitin and acetaminophen-induced liver injury mouse models. Conclusion: Our data suggest that systemic administration of AAT can be a promising therapy to treat acute liver failure and clinical studies to explore this treatment in humans should be initiated. (Hepatology 2014;59:2299–2308)

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