Sympathetic Regulation of Endotoxemia in Drug Abuse

描述：宿主对内毒素血症的防御反应因人而异。可卡因 在某些人类中，使用进一步妥协的微生物感染反应， 尽管导致感染性休克个体易感性的因素 在药物滥用的背景下，这一问题尤其复杂，人们对此了解甚少。它 似乎有多种因素相互作用来决定个体的反应能力 包括对急性炎症反应的自主调节。这 提案是基于可卡因会增强易感性的前提 一些人比其他人更容易发生感染性休克。我们建议 不同的血管对可卡因的反应性在 诱发心血管功能障碍，包括感染性休克综合征 来自革兰氏阴性传染病病原体。同情心的影响， 可卡因，可能对心血管疾病和 病原体诱导的细胞因子基因表达，从而减少在 内毒素血症。在我们的可卡因诱导的心肌病和高血压模型中 在清醒的大鼠中，可卡因引起全身血管的大幅增加 阻力(SysVR)和肾交感神经活动同时发生 指定血管反应者的动物的心输出量(CO)的减少。在……里面 相比之下，混合应答者的SysVR和CO增加较小。 我们的证据表明，血管反应者和混合反应者之间的差异 依赖于不同的中枢神经系统对可卡因的交感反应。我们 假设对可卡因的过度交感反应和 血管反应者记录的内毒素血症导致危及生命的休克 要么是受体敏感性的更大丧失，要么是由于 促炎细胞因子。这项提案将揭示变更的原因。 对急慢性可卡因使用后内毒素血症预后的影响。首先，我们 将证实急性可卡因预处理对 接尘大鼠心血管反应、细胞因子表达及致死性 革兰氏阴性内毒素血症。我们将利用脂多糖(LPS)作为 革兰氏阴性炎症的自限模型。第二，我们将确定 外周肾上腺素能受体与交感神经的作用 对个体敏感性的变化负责的系统 可卡因暴露动物内毒素血症。第三，我们将确定 特异性外周耳廓在调节不同血流动力学和免疫反应中的作用 细胞因子对内毒素的反应。我们将评估促炎症细胞因子的合成 和血浆、肝脏、脾和肺中的水平，并阻断 IL-1B和肿瘤坏死因子-α。第四，我们将研究长期接触铅的影响。 可卡因对急性心肌梗死患者自主神经调节和细胞因子表达的影响 内毒素血症。最后，我们将研究自主和自主的潜在贡献 染毒大鼠细胞因子对内毒素血症易感性的反应 反复吸食可卡因。这些研究将为我们提供对 感染相关心血管功能障碍的发病机制 炎症和阐明交感神经系统在 调节血管张力和细胞因子的反应性。此信息将 有助于我们了解发病的易感因素和 人类感染性休克的严重性和可卡因的使用机制 会影响这一过程。

DESCRIPTION: Host defense responses to endotoxemia vary in individuals. Cocaine use further compromises responses to microbial infections in some humans, although the factors responsible for individual predisposition to septic shock in the context of drug abuse is particularly complex and poorly understood. It appears that multiple factors interact to determine individual responsiveness including autonomic regulation of the acute inflammatory responses. This proposal is based on the premise that cocaine will enhance the predisposition to septic shock more readily in some individuals than others. We propose that divergent vascular responsivity to cocaine plays a pivotal role in the induction of cardiovascular dysfunction, including the septic shock syndrome from Gram-negative infectious agents. The effects of the sympathomimetic, cocaine, are potentially on both cardiovascular derangements and on pathogen-induced cytokine gene expression, thereby reducing survival during endotoxemia. In our model of cocaine-induced cardiomyopathies and hypertension in conscious rats, cocaine evokes substantial increases in systemic vascular resistance (SysVR) and renal sysmpathetic nerve activity concurrent with reductions in cardiac output (CO) in animals designated vascular responders. In contrast, mixed responders have smaller increases in SysVR and increases in CO. Our evidence suggests that differences between vascular and mixed responders depend on divergent CNS-mediated sympathetic responses to cocaine. We hypothesize that the excessive sympathetic responsiveness to cocaine and endotoxemia noted in vascular responders results in life-threatening shock due to either a greater loss in receptor sensitivity or to enhanced expression of pro-inflammatory cytokines. This proposal will reveal the causes of alterations in the prognosis of endotoxemia after acute and chronic cocaine use. First, we will verify that acute cocaine pretreatment differentially affects cardiovascular responses, cytokine expression and lethality in rats exposed to Gram-negative endotoxemia. We will utilize lipopolysaccharide (LPS) as a self-limiting model of Gram-negative inflammation. Second, we will determine the contribution of peripheral adrenergic receptors and the sympathetic nervous system that are responsible for variations in individual sensitivity to LPS-induced endotoxemia in animals exposed to cocaine. Third, we will determine the role of specific peripheral autacoids in mediating variable hemodynamic and cytokine responses to LPS. We will assess proinflammatory cytokine synthesis and levels in the plasma, liver, spleen and lungs and block the actions of IL-1B and TNF-alpha. Fourth, we will examine the effects of chronic exposure to cocaine on patterns of autonomic regulation and cytokine expression to acute endotoxemia. Finally, we will study the potential contribution of autonomic and cytokine responsiveness to susceptibility to endotoxemia in rats exposed to repeated cocaine. These studies will provide novel insights into the pathogenesis of cardiovascular dysfunction during infection-related inflammation and clarify the role of the sympathetic nervous system in modulating vascular tone and cytokine responsivity. This information will contribute to our understanding of predisposing factors to the incidence and severity of septic shock in humans and the mechanisms by which cocaine use affects this process.