Involvement of Natural Killer T Cells in Halothane-induced Liver Injury in Mice

Overview

Journal Biochem Pharmacol

Specialties Biochemistry
Pharmacology

Date 2010 Apr 3

PMID 20359463

Citations 16

Authors

Linling Cheng

Qiang You

Hao Yin

Michael P Holt

Cynthia Ju

Affiliations

Soon will be listed here.

Abstract

Drug-induced liver injury (DILI) causes significant patient morbidity and mortality, and is the most common reason for drug withdrawals. It is imperative to gain a thorough understanding of the underlying mechanisms of DILI to effectively predict and prevent these reactions. We have recently developed a murine model of halothane-induced liver injury (HILI). The aim of the present study was to investigate the role of hepatic natural killer T (NKT) cells in the pathogenesis of HILI. The degrees of HILI were compared between WT and CD1d(-/-) mice, which are deficient in NKT cells. The data revealed that CD1d(-/-) mice were resistant in developing HILI. This resistance appeared to be a direct result of NKT cell depletion rather than an indirect one due to the absence of cross-talk between NKT cells and other hepatic innate immune cells. Compared with WT mice, CD1d(-/-) mice exhibited a significantly lower number of hepatic infiltrating neutrophils upon halothane challenge (470,000+/-100,000/liver in WT vs. 120,000+/-31,500/liver in CD1d(-/-) mice). This result in conjunction with our previous finding of an indispensable role of neutrophils in HILI strongly suggests that NKT cells play a critical role in regulating neutrophil recruitment, thereby contributing to the development of HILI. Collectively, the current study and published reports indicate that this murine model of HILI provides an experimental system for the investigation of the underlying mechanisms of DILI. In addition, this model may yield the discovery of susceptibility factors that may control the development of liver injury in patients treated with halothane and potentially other drugs.

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