Neutrophil depletion protects against murine acetaminophen hepatotoxicity

Authors

  • Zhang-Xu Liu,

    Corresponding author
    1. Research Center for Liver Disease, Department of Medicine, The Keck School of Medicine, University of Southern California, Los Angeles, CA
    • USC Research Center for Liver Disease, 2011 Zonal Avenue, HMR 101, Los Angeles, CA 90033
    Search for more papers by this author
    • fax: 323-442-5425

  • Derick Han,

    1. Research Center for Liver Disease, Department of Medicine, The Keck School of Medicine, University of Southern California, Los Angeles, CA
    Search for more papers by this author
  • Basuki Gunawan,

    1. Research Center for Liver Disease, Department of Medicine, The Keck School of Medicine, University of Southern California, Los Angeles, CA
    Search for more papers by this author
  • Neil Kaplowitz

    1. Research Center for Liver Disease, Department of Medicine, The Keck School of Medicine, University of Southern California, Los Angeles, CA
    Search for more papers by this author

  • See Editorial on Page 1191

  • Potential conflict of interest: Nothing to report.

Abstract

We previously reported that liver natural killer (NK) and NKT cells play a critical role in mouse model of acetaminophen (APAP)-induced liver injury by producing interferon gamma (IFN-γ) and modulating chemokine production and subsequent recruitment of neutrophils into the liver. In this report, we examined the role of neutrophils in the progression of APAP hepatotoxicity. C57BL/6 mice were given an intraperitoneal toxic dose of APAP (500 mg/kg), which caused severe acute liver injury characterized by significant elevation of serum ALT, centrilobular hepatic necrosis, and increased hepatic inflammatory cell accumulation. Flow cytometric analysis of isolated hepatic leukocytes demonstrated that the major fraction of increased hepatic leukocytes at 6 and 24 hours after APAP was neutrophils (Mac-1+Gr-1+). Depletion of neutrophils by in vivo treatment with anti-Gr-1 antibody (RB6-8C5) significantly protected mice against APAP-induced liver injury, as evidenced by markedly reduced serum ALT levels, centrilobular hepatic necrosis, and improved mouse survival. The protection was associated with decreased FasL-expressing cells, cytotoxicity against hepatocytes, and respiratory burst in hepatic leukocytes. In intracellular adhesion molecule (ICAM)-1–deficient mice, APAP caused markedly reduced liver injury when compared with wild-type mice. The marked protection in ICAM-1–deficient mice was associated with decreased accumulation of neutrophils in the liver. Hepatic GSH depletion and APAP-adducts showed no differences among the antibody-treated, ICAM-1–deficient, and normal mice. In conclusion, accumulated neutrophils in the liver contribute to the progression and severity of APAP-induced liver injury. (HEPATOLOGY 2006;43:1220–1230.)

Ancillary