INFLAMMATION AND DRUG IDIOSYNCRASY

描述(由申请人提供)：动物模型有可能预测/早期识别特殊的药物不良反应(IADR)，可以防止人类痛苦，改善药物开发期间的决策和对机制的理解。IADRs可能发生的一种方式是通过药物与炎症应激的相互作用。支持这一假说的是，细菌脂多糖(LPS)在动物体内引起的温和炎症发作与导致人类IADR的药物相互作用，而在人类中没有IADR责任的药物不会。例如，曲伐沙星(TVX)在人体内引起肝毒性IADRs，它与啮齿动物体内的内毒素相互作用导致肝脏损伤。相比之下，左氧氟沙星没有引起人类IADRs，也没有表现出与内毒素的肝毒性相互作用。在目前的授权期间，我们不仅扩大了啮齿动物内毒素-药物相互作用模型的数量，而且发现肿瘤坏死因子-α(TNF)、中性粒细胞(PMN)和止血系统在肝细胞损伤的发病机制中是重要的介质。血管内皮生长因子(VEGF)可以上调所有这些因子的表达，最近的研究结果表明它参与了肝损伤。因此，在下一个授权期内要检验的总体假设是，在脂多糖-药物相互作用过程中增加的血管内皮生长因子的产生通过影响肿瘤坏死因子、中性粒细胞和/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相关药物的相互作用导致肝脏损伤的一连串事件。具体目的是描绘血管内皮生长因子出现的时间进程，以及血管内皮生长因子中和在发病机制中对其他关键事件的影响。我们将在体内阐明血管内皮生长因子与肿瘤坏死因子、中性粒细胞和止血系统的作用的关系，以了解内毒素和TVX作为IADR模型药物共同治疗导致损伤的一连串事件。EGR-1是一种转录因子，控制着血管内皮生长因子的表达，在接受内毒素/药物治疗的动物的肝脏中选择性上调；因此，它在肝毒性级联反应中的作用将部分通过使用EGR-1基因敲除的小鼠来探索。这些研究将继续检验一种新的假说，该假说可以解释肝脏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。与公共卫生相关：特殊的药物不良反应是罕见的，人们对药物的毒性反应知之甚少，这些反应经常损害肝脏，导致人类痛苦，有时甚至死亡。最近发展的动物模型表明，当患者在药物治疗过程中出现炎症反应时，这些反应有时会发生，这些模型可能使预测可能导致此类反应的药物成为可能。这项拟议的研究旨在了解在这些模型中导致肝脏毒性的一连串事件，最终目标是选择更安全的候选药物并开发策略，以减少人类因特殊药物反应而遭受的痛苦。

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.