Animal models with the potential to enable prediction/early identification of idiosyncratic adverse drug reactions (IADRs) could prevent human suffering and improve decision-making during drug development and the understanding of mechanisms. One mode by which IADRs might occur is through interaction of the drug with an inflammatory stress. In support of this hypothesis, a modest inflammatory episode caused by bacterial lipopolysaccharide (LPS) in animals interacts with drugs that cause IADRs in humans to produce liver injury, whereas drugs without IADR liability in people do not. For example, trovafloxacin (TVX) has caused hepatotoxic IADRs in people, and it interacts with LPS in rodents to cause liver injury. In contrast, levofloxacin, which has not caused human IADRs, shows no hepatotoxic interaction with LPS. In the current granting period, we have not only expanded the number of LPS-drug interaction models in rodents but have also identified tumor necrosis factor-alpha (TNF), neutrophils (PMNs) and the hemostatic system as important mediators in the pathogenesis of hepatocellular injury. Vascular endothelial growth factor (VEGF) can upregulate all of these factors, and recent results suggest its involvement in the liver injury. Accordingly, the overall hypothesis to be tested during the next granting period is that enhanced VEGF production during LPS-drug interaction results in liver injury by influencing TNF, PMNs and/or the hemostatic system. A major goal of the proposed research is to elucidate the cascade of events that culminates in liver injury from the interaction of inflammatory stress with IADR-associated drugs.
Specific aims are proposed to delineate the time course of VEGF appearance and the effect of VEGF neutralization on other, critical events in the pathogenesis. The relationship of VEGF to the roles of TNF, PMNs and the hemostatic system will be elucidated in vivo to understand the cascade of events that leads to injury from cotreatment with LPS and TVX as a model IADR-causing drug. Egr-1 is a transcription factor that controls expression of VEGF and is selectively upregulated in livers of LPS/drug-treated animals;accordingly, its role in the hepatotoxic cascade will be explored in part by using egr-1 knockout mice. These studies will continue to test a novel hypothesis that could explain a cause of hepatic IADRs and will increase knowledge of mechanisms of drug interactions with inflammatory stress.
Idiosyncratic adverse drug reactions are rare, poorly understood toxic reactions to drugs that often damage the liver and cause human suffering and sometimes death. Recently developed animal models suggest that these reactions sometimes happen when a patient has an inflammatory response during drug therapy, and these models may enable prediction of drugs that are likely to cause such reactions. The proposed research is aimed at understanding the cascade of events that leads to liver toxicity in these models, with the ultimate goal of choosing safer drug candidates and developing strategies to reduce human suffering from idiosyncratic drug reactions.
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