INFLAMMATION AND DRUG IDIOSYNCRASY

描述（由申请人提供）：具有预测/早期识别特异性药物不良反应（IADRs）潜力的动物模型可以预防人类痛苦，改善药物开发过程中的决策和对机制的理解。可能发生IADRs的一种模式是通过药物与炎症应激的相互作用。为了支持这一假设，动物体内由细菌脂多糖（LPS）引起的轻度炎症发作与引起人类IADR的药物相互作用产生肝损伤，而在人类中没有IADR责任的药物则不会。例如，曲瓦沙星（TVX）在人体内引起肝毒性iadr，并与啮齿动物体内的LPS相互作用导致肝损伤。相比之下，左氧氟沙星没有引起人类IADRs，与LPS没有肝毒性相互作用。在当前的授权期内，我们不仅扩大了啮齿类动物lps -药物相互作用模型的数量，而且还确定了肿瘤坏死因子- α (TNF)、中性粒细胞（pmn）和止血系统是肝细胞损伤发病机制中的重要介质。血管内皮生长因子（VEGF）可以上调所有这些因子，最近的研究结果表明其参与肝损伤。因此，下一个给予期需要检验的总体假设是，在lps -药物相互作用过程中，VEGF生成的增强通过影响TNF、pmn和/或止血系统而导致肝损伤。拟议研究的一个主要目标是阐明炎症应激与iadr相关药物相互作用最终导致肝损伤的级联事件。我们提出了具体的目标来描述VEGF出现的时间过程以及VEGF中和对其他发病机制中关键事件的影响。VEGF与TNF、PMNs和止血系统的作用的关系将在体内得到阐明，以了解与LPS和TVX作为模型iadr引起的药物共同治疗导致损伤的级联事件。Egr-1是一种控制VEGF表达的转录因子，在LPS/药物治疗的动物肝脏中选择性上调；因此，其在肝毒性级联反应中的作用将通过使用egr-1敲除小鼠来部分探索。这些研究将继续测试一种新的假设，该假设可以解释肝脏IADRs的原因，并将增加对药物与炎症应激相互作用机制的了解。公共卫生相关性：特殊药物不良反应是罕见的，对药物的毒性反应知之甚少，通常会损害肝脏并导致人类痛苦，有时甚至死亡。最近开发的动物模型表明，当患者在药物治疗期间出现炎症反应时，有时会发生这些反应，这些模型可以预测可能引起此类反应的药物。拟议的研究旨在了解这些模型中导致肝毒性的级联事件，最终目标是选择更安全的候选药物并制定策略以减少人类遭受特殊药物反应的痛苦。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.