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 使用进一步损害了一些人对微生物感染的反应， 虽然导致感染性休克的因素 在药物滥用的背景下，这一问题特别复杂，人们对此知之甚少。它 似乎多种因素相互作用，以确定个人的反应 包括急性炎症反应的自主调节。这 该提案的前提是可卡因会增强 感染性休克在某些个体中的发生率更高我们建议 血管对可卡因的不同反应性在 诱发心血管功能障碍，包括败血性休克综合征 免受革兰氏阴性病原体感染拟交感神经药的作用， 可卡因，可能对心血管紊乱和 病原体诱导的细胞因子基因表达， 内毒素血症在我们的可卡因诱发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 阻力（SysVR）和肾交感神经活动，同时 在指定血管反应者的动物中心输出量（CO）的减少。在 相反，混合应答者的SysVR增加较小，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CNS介导的对可卡因的交感神经反应。我们 假设对可卡因的过度交感神经反应， 在血管反应者中观察到的内毒素血症导致危及生命的休克， 受体敏感性的更大损失或 促炎细胞因子。这份提案将揭示改变的原因 急性和慢性可卡因使用后内毒素血症的预后。一是 将验证急性可卡因预处理对 暴露于以下物质的大鼠的心血管反应、细胞因子表达和致死率 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性模型。第二，我们将确定 外周肾上腺素能受体和交感神经的作用 系统，负责个体敏感性的变化， 暴露于可卡因的动物中LPS诱导的内毒素血症。第三，我们将确定 特异性外周自体激素在介导可变血流动力学和 细胞因子对LPS的反应。我们将评估促炎细胞因子的合成 血浆、肝、脾和肺中的水平，并阻断 IL-1B和TNF-α。第四，我们将研究长期暴露于 可卡因对急性脑梗死患者自主神经调节模式和细胞因子表达的影响 内毒素血症最后，我们将研究自主神经和 内毒素血症易感性对细胞因子反应性的影响 重复可卡因这些研究将提供新的见解， 感染相关性心血管功能障碍的发病机制 炎症和阐明交感神经系统的作用， 调节血管张力和细胞因子反应性。这些信息将 有助于我们了解发病的诱发因素， 人类感染性休克的严重程度和可卡因使用的机制 影响这个过程。

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.