Coagulation-Mediated Hypoxia and Neutrophil-Dependent Hepatic Injury in Rats Given Lipopolysaccharide and Ranitidine

Luyendyk, James P.; Shaw, Patrick J.; Green, Christopher D.; Maddox, Jane F.; Ganey, Patricia E.; Roth, Robert A.

doi:10.1124/jpet.105.087981

Cited by 50 publications

(63 citation statements)

References 37 publications

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“…Hepatic inflammatory infiltrates in LPS/RAN-treated rats comprised predominantly PMNs, suggesting the possibility of a role for these cells in the liver injury (Luyendyk et al, 2005). In addition, the expression of several genes involved in hemostasis or the response to …”

Section: Ranitidine-induced Idiosyncratic Hepatotoxicity Inmentioning

confidence: 99%

“…Cotreatment with either anticoagulant heparin, the fibrinolytic agent streptokinase, or a PAI-1 inhibitor decreased the hepatocellular injury induced by LPS/RAN, suggesting a role for the hemostatic system . Hepatic hypoxia occurred in LPS/RAN-treated rats, and heparin reduced the tissue hypoxia and fibrin deposition (Luyendyk et al, 2005). RAN seems to selectively augment coagulation and PAI-1 production triggered by LPS, and this in turn causes fibrin deposition that leads to tissue hypoxia and hepatocyte death.…”

Section: Involvement Of Hemostasis Neutrophils and Tumor Necrosis Fmentioning

confidence: 99%

“…Such features could include increased sensitivity of hepatocytes to PMNderived proteases. For example, when isolated hepatocytes were exposed to PMN proteases in a hypoxic environment, damage occurred more rapidly than in an oxygen-replete environment (Luyendyk et al, 2005). Moreover, PMN protease inhibitors protected the liver from injury caused by ischemia-reperfusion, although this attenuation was accompanied by a decrease in circulating chemokines and hepatic PMN accumulation (Yamaguchi et al, 1997).…”

Section: Neutrophilsmentioning

confidence: 99%

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Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

et al. 2009

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Section: Ranitidine-induced Idiosyncratic Hepatotoxicity Inmentioning

confidence: 99%

Section: Involvement Of Hemostasis Neutrophils and Tumor Necrosis Fmentioning

confidence: 99%

Section: Neutrophilsmentioning

confidence: 99%

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Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

et al. 2009

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“…37 Toxicity was accompanied by a marked neutrophil infi ltration and inhibited by depletion of neutrophils with antineutrophil antibodies. 38 Toxicity was also associated with fi brin deposition and inhibited by heparin. This data suggest that LPS-potentiated toxicity involves a combination of fi brin deposit-induced hypoxia and neutrophil-mediated cell damage.…”

Section: Lipopolysaccaride-potentiated Hepatotoxicitymentioning

confidence: 98%

“…This data suggest that LPS-potentiated toxicity involves a combination of fi brin deposit-induced hypoxia and neutrophil-mediated cell damage. 38 It was suggested that this could be a dominant mechanism for hepatic DHRs, and that random exposure to LPS or other infl ammatory condition could explain the time course of DHRs. 39 Although neutrophils can be part of the cellular infi ltrate in hepatic DHRs, the dominant cells are usually mononuclear.…”

Section: Lipopolysaccaride-potentiated Hepatotoxicitymentioning

confidence: 99%

Role of animal models in the study of drug-induced hypersensitivity reactions

Uetrecht

2005

AAPS J

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A BSTRACTDrug-induced hypersensitivity reactions (DHRs) are a major problem, in large part because of their unpredictable nature. If we understood the mechanisms of these reactions better, they might be predictable. Their unpredictable nature also makes mechanistic studies very diffi cult, especially prospective clinical studies. Animal models are vital to most biomedical research, and they are almost the only way to test basic hypotheses of DHRs, such as the involvement of reactive metabolites. However, useful animal models of DHRs are rare because DHRs are also unpredictable in animals. For example, sulfonamide-induced DHRs in large-breed dogs appear to be valid because they are very similar to the DHRs that occur in humans; however, the incidence is only ~0.25%, and large-breed dogs are diffi cult to use as an animal model. Two more practical models are penicillamine-induced autoimmunity in the Brown Norway rat and nevirapine-induced skin rash in rats. The toxicity in these models is clearly immune mediated. In other models, such as amodiaquineinduced agranulocytosis/hepatotoxicity and halothaneinduced hepatotoxicity, the drug induces an immune response but there is no clinical toxicity. This fi nding suggests that regulatory mechanisms usually limit toxicity. Many of the basic characteristics of the penicillamine and nevirapine models, such as memory and tolerance, are quite different suggesting that the mechanisms are also signifi cantly different. More animal models are needed to study the range of mechanisms involved in DHRs; without them, progress in understanding such reactions is likely to be slow. K EYWORDS: animal models , hypersensitivity reactions , idiosyncratic drug reactions , penicillamine , nevirapine , popliteal lymph node assay INTRODUCTIONTo an immunologist, the term hypersensitivity implies an immune-mediated reaction. The term drug-induced hypersensitivity reaction (DHR) is used to describe a syndrome consisting of fever, rash, and involvement of various organs associated with drugs such as phenytoin, carbamazepine, abacavir, sulfonamides, and allopurinol; however, it is also frequently used to describe any idiosyncratic drug reaction. For many of the adverse reactions to be discussed in this review, it has not been conclusively demonstrated that they are immune mediated, and the term hypersensitivity reaction will be used broadly to refer to any idiosyncratic drug reaction that has features that suggest it is immune mediated. Another working hypothesis for this review, which is supported by a large amount of circumstantial evidence, 1 but in virtually no case proven, is that most DHRs are caused by reactive metabolites. Therefore, a major role of animal models is to test whether reactive metabolites are responsible for hypersensitivity reactions and further to determine how reactive metabolites provoke an immune response.A major characteristic of DHRs is their unpredictable or idiosyncratic nature. This means that at the present time it is impossible to predict which drug candidates will...

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Inflammation and Drug‐Induced Liver Injury

Roth

Ganey

2009

The Liver

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Coagulation-Mediated Hypoxia and Neutrophil-Dependent Hepatic Injury in Rats Given Lipopolysaccharide and Ranitidine

Cited by 50 publications

References 37 publications

Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

Role of animal models in the study of drug-induced hypersensitivity reactions

Inflammation and Drug‐Induced Liver Injury

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