A pivotal involvement of IFN‐' in the pathogenesis of acetaminophen‐induced acute liver injury

Ishida, Yuko; Kondo, Toshikazu; Ohshima, Tohru; Fujiwara, Hiromi; Iwakura, Yoichiro; Mukaida, Naofumi

doi:10.1096/fj.02-0046com

Cited by 205 publications

(246 citation statements)

References 32 publications

Supporting

Mentioning

233

Contrasting

Order By: Relevance

“…We previously observed that the increases in serum ALT levels preceded neutrophil infiltration into liver in APAPinduced acute hepatotoxicity [13,14]. These observations raised questions on the pathogenic roles of neutrophil infiltration in APAP-induced liver dysfunction.…”

Section: Resultsmentioning

confidence: 98%

“…In line with this assumption, accumulating evidence has implicated neutrophils as the leukocyte type essentially involved in the pathogenesis of various liver diseases [8][9][10][11][12]. However, we previously observed that the increases in serum alanine transferase (ALT) levels preceded neutrophil infiltration into liver in APAPinduced liver injury [13,14]. Inactivation of neutrophils by anti-CD18 Ab had no effects on APAP-induced liver injury [15].…”

Section: Introductionmentioning

confidence: 94%

“…[8][9][10][11][12][31][32][33][34][35]. However, our previous observations that liver dysfunction preceded neutrophil infiltration in APAP-induced liver injury [13,14], prompted us to investigate the pathogenic roles of neutrophils, using the anti-granulocyte Ab. Here, we demonstrated that depletion of neutrophils from peripheral blood prevented the development of APAP-induced liver injury as well as neutrophil infiltration almost completely.…”

Section: The Roles Of Ho-1 In Apap-induced Liver Injurymentioning

confidence: 99%

“…Several lines of evidence demonstrated that the recruitment of neutrophils was significantly reduced in some disease models using mice lacking CXC chemokine receptor 2 (CXCR2), a receptor for CXCL1 and CXCL2 [19][20][21][22][23][24][25][26]. Our previous study demonstrated that the magnitude of liver injury induced by APAP well correlated with intrahepatic neutrophil number and intrahepatic myeloperoxidase activity, suggesting that neutrophil recruitment was involved in the pathogenesis of APAP-induced liver injury [13,14].…”

Section: Introductionmentioning

confidence: 99%

“…Both Ly-6G-treated neutropenic WT mice and CXCR2-KO mice showed attenuated APAP-induced liver injury, with reduced neutrophil infiltration. Moreover, we demonstrated that neutrophils expressed CXCR2 and inducible NO synthase (iNOS), which can produce NO, a potent injurious mediator for APAP-induced liver injury [13].When compared between neutropenic WT and CXCR2-KO mice, the latter were less resistant to APAP-induced hepatotoxicity, with less macrophage infiltration. We further showed that a substantial portion of macrophages expressed CXCR2 and that macrophages were a major source of heme oxygenase (HO)-1, which exhibits protective activities for various liver injuries including APAP-induced liver injury [27][28][29][30].…”

mentioning

confidence: 98%

See 4 more Smart Citations

Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen‐induced acute liver injury

et al. 2006

Self Cite

View full text Add to dashboard Cite

Neutrophils and macrophages infiltrate after acetaminophen (APAP)-induced liver injury starts to develop. However, their precise roles still remain elusive. In untreated and control IgG-treated wild-type (WT) mice, intraperitoneal APAP administration (750 mg/kg) caused liver injury including centrilobular hepatic necrosis and infiltration of neutrophils and macrophages, with about 50% mortality within 48 h after the injection. APAP injection markedly augmented intrahepatic gene expression of inducible nitric oxide synthase (iNOS) and heme oxygenase (HO)-1. Moreover, neutrophils expressed iNOS, which is presumed to be an aggravating molecule for APAP-induced liver injury, while HO-1 was mainly expressed by macrophages. All antigranulocyte antibody-treated neutropenic WT and most CXC chemokine receptor 2 (CXCR2)-deficient mice survived the same dose of APAP, with reduced neutrophil infiltration and iNOS expression, indicating the pathogenic roles of neutrophils in APAPinduced liver injury. However, APAP caused more exaggerated liver injury in CXCR2-deficient mice with reduced macrophage infiltration and HO-1 gene expression, compared with neutropenic WT mice. An HO-1 inhibitor, tin-protoporphyrin-IX, significantly increased APAP-induced mortality, implicating HO-1 as a protective molecule for APAP-induced liver injury. Thus, CXCR2 may regulate the infiltration of both iNOS-expressing neutrophils and HO-1-expressing macrophages, and the balance between these two molecules may determine the outcome of APAP-induced liver injury. IntroductionAcetaminophen (APAP) is widely prescribed as an analgesic and antipyretic drug in clinics and is also sold as numerous over-counter preparations as a single compound or in combination with other medications [1, 2]. Although it is generally safe, an overdose of APAP can cause severe liver failure with a significant morbidity and mortality. Thus, its wide availability and severe toxicities has placed APAP overdose as the leading cause for calls to Poison Control Centers in the United States (>100 000/year). Moreover, APAP overdose accounts for more than 56 000 emergency room visits, 2600 hospitalizations, and an estimated 458 deaths due to acute liver failure each year in the United States alone [3]. The toxic response is initiated by the metabolism of APAP to a toxic metabolite, N-acetyl-p-benzoquinone imine. Because N-acetyl-p-benzoquinone imine can react rapidly with sulfhydryl groups, it first depletes glutathione in hepatocytes and then reacts with a number of intracellular proteins, thereby causing their dysfuntions [4, 5]. APAP-induced liver injury is histopathologically characterized by centrilobular hepatic necrosis with a massive infiltration of leukocytes, particularly neutrophils. The recruitment of leukocytes in the damaged tissue is a hallmark of the inflammatory process, which may contribute to the development of APAP-induced liver injury [6,7]. In line with this assumption, accumulating evidence has implicated neutrophils as the leukocyte type essentially involved i...

show abstract

Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 94%

Section: The Roles Of Ho-1 In Apap-induced Liver Injurymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 98%

See 3 more Smart Citations

Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen‐induced acute liver injury

et al. 2006

Self Cite

View full text Add to dashboard Cite

show abstract

Drug Bioactivation and Oxidative Stress

Webb

Regan

Antoine

et al. 2012

Encyclopedia of Drug Metabolism and Interactions

View full text Add to dashboard Cite

Adverse drug reactions (ADRs) remain a major complication of drug therapy, account for a significant number of hospital admissions each year and contribute to patient morbidity and mortality. These reactions are a major issue for the pharmaceutical industry, accounting for attrition of approximately one third of compounds in development. Drug toxicity can mimic natural disease and almost any body system can be adversely affected by drugs. However, off‐target or idiosyncratic drug reactions represent a major problem for the pharmaceutical industry because they add significant uncertainty to the process of drug development and can ultimately lead to drug withdrawal or warnings in drug labelling. They are particularly difficult to deal with because they are likely to be discovered late in development or after the drug has been approved; this has important implications as the latter a drug fails, the more expensive is the failure. Excessive dose, drug accumulation and/or the formation of chemically reactive metabolites (CRMs) have been implicated in many ADRs. Such reactions are usually rare and are not evident in animal species, but they can be serious and even fatal in humans and may lead to the withdrawal of otherwise effective therapeutic agents. The fear of such reactions occurring at the post‐approval stage, when such problems typically first become evident is a major impediment to drug development. At present, during preclinical drug evaluation there are no accepted methods for the identification of drugs that may cause hypersensitivity or idiosyncratic drug reactions in humans. The focus of this chapter will be to examine the formation and identification of CRMs through the normal process of phase I and II drug metabolism, elucidate whether these chemically reactive species are toxic, or harmlessly detoxified and excreted and finally to determine if there are any chemical or biological hallmarks of hazard or the development of toxicity, that can be used to more effectively screen out potentially dangerous compounds earlier in the drug development process. This chapter will use case‐study examples of compounds or drugs which have been implicated in a number of off‐target ADRs in humans.

show abstract