Acetaminophen-induced hepatic neutrophil accumulation and inflammatory liver injury in CD18-deficient mice

Liver Int. 2010 Oct;30(9):1280-92. doi: 10.1111/j.1478-3231.2010.02284.x.


Background: Acetaminophen (APAP) hepatotoxicity is currently the most frequent cause of acute liver failure in the US and many European countries. Although intracellular signalling mechanisms are critical for hepatocellular injury, a contribution of inflammatory cells, especially neutrophils, has been suggested. However, conflicting results were obtained when using immunological intervention strategies.

Aims: The role of neutrophils was investigated using a CD18-deficient mouse model.

Results: Treatment of C57Bl/6 wild type mice with 300 mg/kg APAP resulted in severe liver cell necrosis at 12 and 24 h. This injury was accompanied by formation of cytokines and chemokines and accumulation of neutrophils in the liver. However, there was no difference in the inflammatory response or liver injury in CD18-deficient mice compared with wild-type animals. In contrast to treatment with endotoxin, no upregulation of CD11b or priming for reactive oxygen was observed on neutrophils isolated from the peripheral blood or the liver after APAP administration. Furthermore, animals treated with endotoxin 3 h after APAP experienced an exaggerated inflammatory response as indicated by substantially higher cytokine and chemokine formation and twice the number of neutrophils in the liver. However, liver injury in the two-hit model was the same as with APAP alone.

Conclusions: Our data do not support the hypothesis that neutrophils contribute to APAP hepatotoxicity or that a neutrophil-mediated injury phase could be provoked by a second, pro-inflammatory hit. Thus, APAP-induced liver injury in mice is dominated by intracellular mechanisms of cell death rather than by neutrophilic inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetaminophen / toxicity*
  • Analgesics, Non-Narcotic / toxicity*
  • Animals
  • Biomarkers
  • CD18 Antigens / genetics*
  • Chemical and Drug Induced Liver Injury / etiology*
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / pathology
  • Chemokines / genetics
  • Chemokines / metabolism
  • Endotoxins / toxicity
  • Female
  • Gene Expression / drug effects
  • Hepatocytes / drug effects
  • Hepatocytes / pathology
  • Injections, Intraperitoneal
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Liver Function Tests
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Necrosis / chemically induced
  • Neutrophils / metabolism*
  • Neutrophils / pathology
  • Oxidative Stress / drug effects
  • RNA, Messenger / metabolism


  • Analgesics, Non-Narcotic
  • Biomarkers
  • CD18 Antigens
  • Chemokines
  • Endotoxins
  • RNA, Messenger
  • Acetaminophen