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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-␥) 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. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

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Drug-induced hepatotoxicity is an important cause of liver disease with significant medical, economic, legal, and regulatory implications. Clinically, it presents a diagnostic challenge to health care professionals since drug-induced liver disease can mimic the clinicopathologic features of all other acute and chronic liver diseases. However, individual drugs tend to have a characteristic clinical signature. Early identification of hepatotoxicity by either laboratory monitoring or patients' awareness as a result of education may avert serious liver injury in delayed idiosyncratic toxicity. Most adverse hepatic reactions require metabolism of the drug to reactive metabolites and free radicals, which then either lead to direct overwhelming lethal insult, nonlethal sensitization to the lethal effects of the innate immune system, or haptenization eliciting an immunoallergic response of the adaptive immune system. Besides licensed drugs, herbal and natural supplements are recognized as causing hepatotoxicity with increasing frequency as patients turn more and more to alternative medicine.

SUMMARY BackgroundPatients with decompensated cirrhosis are at risk for hyperfibrinolysis; this is potentially fatal. e-aminocaproic acid has been used to treat patients with hyperfibrinolysis; however, the data about its benefit in the setting of cirrhosis are minimal.