PXR-Mediated Xenobiotic Response in the Pathogenesis Hemorrhagic Shock

失血性休克发病机制中PXR介导的异种生物反应 项目摘要/摘要： 本研究的目的是了解异种受体孕烷X受体(PXR)在卵巢癌中的作用。 失血性休克的发病机制及临床转归。HS通常是一种危及生命的疾病 与创伤性损伤有关。严重的HS会导致多个组织的损伤，包括肝脏。在……里面 除了肝脏损伤外，HS和由此产生的组织低灌注还会引发一连串的炎症和 氧化应激，导致肝脏药物代谢的全面抑制。房协的反应 抑制肝脏药物代谢具有潜在的临床意义，因为严重创伤 患者被统一开出多种药物的处方。 PXR是异种生物反应的主要调节者，它通过转录调控I期和 二期药物代谢酶(DME)和转运体，特别是在肝脏中。除了诱使 细胞色素P450(CYP)酶，PXR激活的另一个潜在结果是增加 活性氧物种(ROS)是CYP介导的氧化增加的结果。许多药物经常 在创伤发生之前或之后开给HS患者的处方，如RIF和DEX，是已知的PXR 肝脏中的激活剂和二甲醚诱导剂。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环境下的肝脏药物代谢，如果是，激活PXR是有益的还是 不利于HS应激性肝损伤。 我们的初步结果表明：1)应激小鼠表现出PXR和肝脏的动态调节 P450酶，如Cyp3a11；2)HS抑制咪达唑仑和羟考酮的代谢 创伤护理常用药物；3)转基因小鼠中PXR的基因激活使小鼠对HS-R敏感。 应激性肝损伤，但对HS应激性肺损伤影响不大；4)HS应激性肝损伤，但 5)转基因PXR对HS诱导的小鼠的致敏作用 6)PXR转基因对HS应激性肝损伤的增敏作用是 与肝脏氧化应激增加有关；7)hPXR-hCYP3A4人源化小鼠 8)组成雄烷受体(CAR)的激活不影响HS应答性肝损伤。 基于这些观察，我们提出了失血性休克和失血性休克之间的相互作用。 肝脏药物代谢或肝脏药物代谢的调节。具体来说，我们假设 1)HS引起肝损伤，对PXR、CyP3A等基因的表达有动态影响 DMES；2)PXR的激活通过诱导HSP70的表达而增敏HS应激性肝损伤。 细胞色素P3A和不断增加的氧化应激。我们提出了三个具体目标来验证我们的假设：1) 确定PXR在人源化小鼠体内的药理激活是否使其对HS诱导的肝脏敏感 2)确定在人源化小鼠中是否需要CYP3A4的表达和调控 PXR对HS所致肝损伤的增敏作用；3)确定氧化诱导是否 应激是PXR对HS诱导的人源化小鼠肝损伤的增敏作用的机制之一。 综上所述，我们的结果表明，对PXR的HS反应性抑制可能代表着一种保护性的 对HS诱导的肝损伤的反应和/或继发性反应。PXR激动剂的使用不可避免 在HS之前或在创伤的临床处理期间可能会恢复药物代谢，但有可能 加重创伤患者HS诱导的肝损伤，联合应用抗-HBs可减轻这一损伤 氧化剂或PXR拮抗剂。

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.