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Macrophage inflammatory protein-2 gene therapy attenuates adenovirus- and acetaminophen-mediated hepatic injury

Gene Therapy volume 6, pages 573–584 (1999)Cite this article

Abstract

Profound hepatocellular injury is often a consequence of adenovirus-mediated gene therapy or acetaminophen ingestion. The aim of the present study was to examine the role of a CXC chemokine, macrophage inflammatory protein-2 (MIP-2), in the hepatotoxic response by mice infected with adenovirus and challenged with acetaminophen. CD1 mice that received a replication-defective human type 5 adenovirus vector (Ad70-3) intravenously exhibited hepatic injury that peaked at 24 h after infection. In contrast, mice that received a similar adenovirus vector containing a rodent MIP-2 cDNA insert had no hepatic injury at any time after infection. The combination of Ad70-3 infection and an intraperitoneal challenge with 400 mg/kg of acetaminophen was fatal in 50% of the mice, but only 10% of the AdMIP-2 group receiving acetaminophen were similarly affected. Furthermore, AdMIP-2 mice had significantly lower hepatic injury and serum aminotransaminases compared with the Ad70-3 group. However, AdMIP-2 infection in mice lacking the CXC chemokine receptor that binds MIP-2, CXCR2, did not attenuate any of the markers of liver injury after adenovirus and acetaminophen challenge. AdMIP-2 treatment of CD1 mice was also associated with significantly decreased leukocyte infiltration into the liver and an earlier increase in hepatic 3H-thymidine incorporation compared with the control group. Taken together, these data demonstrate that MIP-2 has a protective role in both adenovirus- and acetaminophen-mediated hepatotoxicity, and suggest that MIP-2 may promote rapid hepatic regeneration following acute hepatic injury.

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Authors and Affiliations

  1. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

    C M Hogaboam, K J Simpson, S W Chensue, M L Steinhauser, N W Lukacs & S L Kunkel

  2. Department of Pathology, Veteran Affairs Medical Center, Ann Arbor, MI, USA

    S W Chensue

  3. Department of Pathology, McMaster University, Hamilton, ON, Canada

    J Gauldie

  4. Division of Pulmonary and Critical Care, Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA

    R M Strieter

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Hogaboam, C., Simpson, K., Chensue, S. et al. Macrophage inflammatory protein-2 gene therapy attenuates adenovirus- and acetaminophen-mediated hepatic injury. Gene Ther 6, 573–584 (1999). https://doi.org/10.1038/sj.gt.3300858

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