Role of neutrophils in a mouse model of halothane-induced liver injury

Abstract

Drug-induced liver injury (DILI) is a major safety concern in drug development. Its prediction and prevention have been hindered by limited knowledge of the underlying mechanisms, in part the result of a lack of animal models. We developed a mouse model of halothane-induced liver injury and characterized the mechanisms accounting for tissue damage. Female and male Balb/c, DBA/1, and C57BL/6J mice were injected intraperitoneally with halothane. Serum levels of alanine aminotransferase and histology were evaluated to determine liver injury. Balb/c mice were found to be the most susceptible strain, followed by DBA/1, with no significant hepatotoxicity observed in C57BL/6J mice. D rug-induced liver injury (DILI) represents a major health problem that challenges not only health care professionals but also the pharmaceutical industry and drug-regulatory agencies. In the United States, DILI accounts for as many as 25% of liver failure cases in intensive care units. 1 Due to its association with significant patient morbidity and mortality, DILI is currently the most common cause for the withdrawal of drugs from the pharmaceutical market. 2 The key to predicting and preventing DILI is a thorough understanding of the underlying mechanisms. Prospective human clinical trials would be impossible given the unpredictable nature and low incidence of DILI. Retrospective studies may be conducted; however, they will not yield mechanistic information on the development of DILI. In vitro experiments may be used as a means to understand isolated events in DILI development, but these experiments are not likely to provide insights into the complex molecular and cellular mechanisms of DILI. The best approach for these purposes is to perform animal studies.At present, the only widely studied model of DILI is the acetaminophen (APAP)-induced liver injury model, particularly in mice. Although important information on the mechanism(s) of drug-induced acute inflammatory injury has been obtained using this model, 3-10 APAP hepatotoxicity in mice or humans does not encompass the complete clinical spectrum nor all possible mechanistic

Idiosyncratic Adverse Drug Reactions: Current Concepts

“…Investigators were able to induce an immune response to halothane in Guinea pigs with mild liver injury, but the response decreased with repeated challenges (Furst and Gandolfi, 1997;Furst et al, 1997a,b). Intraperitoneal injection of halothane in oil induced liver injury in mice and generated an innate immune response (You et al, 2006). Mouse strain-, age-, and sex-dependent variations in the severity of this injury were observed, including female sex and older age (Cheng et al, 2009You et al, 2010), which are analogous to the risk factors in humans.…”

A Mouse Model of Severe Halothane Hepatitis Based on Human Risk Factors

“…In a mouse model of mild halothane-induced hepatotoxicity, rabbit antiserum depleted PMNs and attenuated the increase in plasma ALT activity (You et al, 2006). CD18 is an integrin on leukocyte plasma membranes and is needed for adhesion to vascular endothelium and transmigration of PMNs into the liver parenchyma.…”

“…at ASPET Journals on May 9, 2018 jpet.aspetjournals.org liver injury has been either modest (You et al, 2006) or nonexistent (Ong et al, 2007). For example, nevirapine produces idiosyncratic dermal and liver toxicity in humans; a rat model reproduced the skin lesions but failed to reproduce the liver toxicity (Shenton et al, 2003).…”

“…If the major risk factors could be incorporated into an animal model, it follows that liver injury would occur with high frequency. Animal models of halothane hepatotoxicity have been developed, but most reproduce the mild type of injury (Lind et al, 1990;Bourdi et al, 2001;You et al, 2006). Attempts to develop animal models of severe, halothane-induced hepatotoxicity have focused on using repeated exposures (Hastings et al, 1995), drug-metabolizing enzyme inducers, glutathione depletion techniques, and/or hypoxic conditions (McLain et al, 1979;Lind et al, 1992).…”

“…High incidence of severe halothane-induced liver injury (N ϭ 4) was reported in studies using female strain 2 guinea pigs (Lind et al, 1987), but few studies have followed the original report. Starting with knowledge gained from a mouse model of mild halothaneinduced liver injury (You et al, 2006), we explored several known and likely human risk factors in developing a model of halothane hepatitis. The result is the first animal model in which severe halothane-induced liver injury occurs reproducibly without extensive chemical manipulations and that demonstrates histopathologic findings consistent with those observed in humans.…”