Natural Killer Cells Mediate Severe Liver Injury in a Murine Model of Halothane Hepatitis

• DOI: 10.1093/toxsci/kfr005
• Publication Date: 2011-01-19T05:35:53Z
• Authors: Christine M. Dugan; Aaron M. Fullerton; Robert A. Roth; Patricia E. Ganey
• Keywords: Autoimmune Hepatitis; Splenocyte; Knockout mouse

Severe halothane (HAL)-induced hepatotoxicity occurs in one 6000–30,000 patients by an unknown mechanism. Female sex is a risk factor humans and rodents. We tested the hypothesis that difference natural killer (NK) cell activity contributes to HAL-induced liver injury. HAL (15 mmol/kg, ip) treatment resulted severe injury 12 h female, wild-type BALB/cJ mice, magnitude of varied with stage estrous cycle. Ovariectomized (OVX) mice developed only mild Plasma interferon-gamma (IFN-γ) was elevated 10-fold HAL-treated females compared similarly treated male or OVX female mice. IFN-γ knockout were resistant The deactivation NK cells anti-asialo GM1 attenuated increase plasma immunoglobulin G–treated control Mice mutated form perforin, protein involved granule-mediated cytotoxicity, protected from Furthermore, increased vivo, as indicated surface expression CD69, early activation marker. In response HAL, receptor ligands on hepatocytes expressed manner can activate cells. These results confirm sexual dimorphic hepatotoxic suggest have essential roles development hepatotoxicity.