PXR-Mediated Xenobiotic Response in the Pathogenesis Hemorrhagic Shock

失血性休克发病机制中 PXR 介导的异生素反应

• 批准号: 10302289
• 负责人: Wen Xie
• 金额: $ 35.21万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302289
• 关键词: Ablation; Antioxidants; Attenuated; CYP3A4 gene; Clinical; Clinical Management; Cytochrome P450; Data; Drug Targeting; Drug usage; Ensure; Enzymes; Exhibits; Genetic; Goals; Hemorrhagic Shock; Hepatic; Inflammatory; Injury; Knock-out; Lead; Life; Liver; Mediating; Metabolism; Midazolam; Molecular; Mus; N-Acetylcysteinamide; Outcome; Oxidative Stress; Oxidative Stress Induction; Oxycodone; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Play; Production; Reactive Oxygen Species; Receptor Activation; Regulation; Reporting; Role; Testing; Tissues; Transcriptional Regulation; Transgenes; Transgenic Mice; Trauma; Trauma patient; Traumatic injury; Xenobiotics; antagonist; base; constitutive androstane receptor; drug metabolism; humanized mouse; injured; liver injury; lung injury; new therapeutic target; oxidation; pregnane X receptor; primary outcome; response; tempol; trauma care

Title: PXR-Mediated Xenobiotic Response in the Pathogenesis Hemorrhagic Shock Project Summary/Abstract: The goal of this proposal is to understand the role of xenobiotic receptor pregnane X receptor (PXR) in the pathogenesis and clinical outcome of hemorrhagic shock (HS). HS is a life-threatening condition often associated with traumatic injuries. Severe HS can lead to injury to multiple tissues, including the liver. In addition to the liver injury, HS and the resulting tissue hypofusion also induce a cascade of inflammatory and oxidative stress, leading to an overall suppression of drug metabolism in the liver. The HS-responsive suppression of hepatic drug metabolism has potential clinical implications, because seriously injured trauma patients are uniformly prescribed with multiple medications. PXR is a master regulator of xenobiotic response through its transcriptional regulation of the phase I and phase II drug-metabolizing enzymes (DMEs) and transporters, especially in the liver. In addition to inducing cytochrome P450 (CYP) enzymes, another potential outcome of PXR activation is the increased production of reactive oxygen species (ROS) as a result of increased CYP-mediated oxidations. Many of the drugs often prescribed to the HS patients before or after the occurrence of trauma, such as RIF and DEX, are known PXR activators and DME inducers in the liver. It has also been reported that the expression and activity of PXR decreased in experimental HS. However, it is unclear whether PXR plays a role in the regulation of hepatic drug metabolism in the setting of HS and if so, whether activation of PXR is beneficial or detrimental to the HS-responsive liver injury. Our preliminary results showed that: 1) Mice subjected to HS exhibit a dynamic regulation of PXR and hepatic P450 enzymes, such as the Cyp3a11; 2) HS suppresses the metabolism of midazolam and Oxycodone, two drugs commonly used in trauma care; 3) Genetic activation of PXR in transgenic mice sensitizes mice to HS- responsive liver injury, but had little effect on HS-responsive lung injury; 4) The HS-responsive liver injury, but not lung injury, was attenuated in Pxr-/- mice; 5) The sensitizing effect of the PXR transgene on HS-induced liver injury is Cyp3a dependent; 6) The sensitizing effect of the PXR transgene on HS-responsive liver injury is associated with increased hepatic oxidative stress; 7) The hPXR-hCYP3A4 humanized mice have been created; and 8) Activation of constitutive androstane receptor (CAR) does not affect HS-responsive liver injury. Based on these observations, we propose a reciprocal interaction between hemorrhagic shock (HS) and hepatic drug metabolism or the regulation of hepatic drug metabolism. Specifically, we hypothesize that 1) HS causes liver damage and has a dynamic effect on the expression of PXR, CYP3A and other DMEs; and 2) Activation of PXR sensitizes HS-responsive liver injury by inducing the expression of CYP3A and increasing oxidative stress. We propose three specific aims to test our hypotheses: 1) To determine whether pharmacological activation of PXR in humanized mice sensitizes them to HS-induced liver injury; 2) To determine whether the expression and regulation of CYP3A4 in humanized mice are required for the sensitizing effect of PXR on HS-induced liver injury; and 3) To determine whether the induction of oxidative stress is responsible for the sensitizing effect of PXR on HS-induced liver injury in humanized mice. Taken together, our results suggest that the HS-responsive suppression of PXR may represent a protective response and/or secondary response to HS-induced liver injury. The unavoidable use of PXR-activating drugs prior to HS or during the clinical management of trauma may restore drug metabolism, but has the potential to exacerbate HS-induced liver injury in trauma patients, which can be mitigated by the co-administration of anti- oxidative agents or PXR antagonists.

标题：出血性休克发病机制中PXR介导的外源性反应 项目概要/摘要： 本提案的目的是了解异生素受体PXR在细胞凋亡中的作用。 出血性休克（HS）的发病机制和临床结局。HS是一种危及生命的疾病， 与外伤有关严重的HS可导致多个组织损伤，包括肝脏。在 除了肝损伤外，HS和由此产生的组织融合不足还诱导了一系列炎性反应， 氧化应激，导致肝脏中药物代谢的总体抑制。HS响应 肝脏药物代谢的抑制具有潜在的临床意义，因为严重的创伤 患者被统一地开出多种药物。 PXR是异生物质反应的主要调节因子，通过其I相和II相的转录调节。 II期药物代谢酶（DME）和转运蛋白，特别是在肝脏中。除了诱导 细胞色素P450（CYP1A1）酶，PXR活化的另一个潜在结果是增加的 活性氧（ROS）是CYP介导的氧化作用增加的结果。许多药物经常 在创伤发生之前或之后给HS患者开的处方，例如RIF和DEX，是已知的PXR 激活剂和DME诱导剂。也有报道称，PXR的表达和活性 在实验性HS中降低。然而，目前尚不清楚PXR是否在调节 HS背景下的肝脏药物代谢，如果是，PXR激活是否有益或 对HS反应性肝损伤有害。 初步结果表明：1）HS对小鼠PXR和肝脏的影响是动态的， P450酶，如Cyp3a11; 2）HS抑制咪达唑仑和羟考酮的代谢， 创伤护理中常用的药物; 3）转基因小鼠中PXR的遗传激活使小鼠对HS-敏感 HS-反应性肝损伤，但对HS-反应性肺损伤影响不大; 4）HS-反应性肝损伤，但对HS-反应性肺损伤影响不大。 5）PXR转基因对HS诱导的肺损伤的致敏作用在Pxr-/-小鼠中减弱; 肝损伤是Cyp3a依赖性的; 6）PXR转基因对HS应答性肝损伤的增敏作用是 7）hPXR-hCYP3A4人源化小鼠已被证实与肝氧化应激增加相关; 8）组成型雄烷受体（CAR）的激活不影响HS-应答性肝损伤。 基于这些观察结果，我们提出了失血性休克（HS）和 肝脏药物代谢或肝脏药物代谢的调节。具体来说，我们假设 结论：1）HS可引起肝损伤，并对PXR、CYP3A等的表达产生动态影响， DME;和2）PXR的活化通过诱导DMEs的表达而使HS-应答性肝损伤敏感化。 CYP3A和氧化应激增加。我们提出了三个具体目标来验证我们的假设：1） 确定人源化小鼠中PXR的药理学激活是否使它们对HS诱导的肝敏感 2）确定CYP3A4在人源化小鼠中的表达和调节是否是损伤所必需的。 PXR对HS诱导的肝损伤的增敏作用; 3）确定是否诱导氧化损伤， 应激是PXR对HS诱导的人源化小鼠肝损伤的致敏作用的原因。 综上所述，我们的结果表明，HS-反应性抑制PXR可能代表了一种保护性机制， 对HS诱导的肝损伤的应答和/或继发应答。不可避免地使用PXR激活药物 在HS之前或在创伤的临床管理期间，可以恢复药物代谢，但有可能 加重创伤患者HS诱导的肝损伤，可通过联合给予抗- 氧化剂或PXR拮抗剂。