Sympathetic Regulation of Endotoxemia in Drug Abuse

药物滥用中内毒素血症的交感调节

• 批准号: 6719034
• 负责人: MARK M KNUEPFER
• 金额: $ 29.11万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6719034
• 关键词: adrenergic receptor; cardiac output; catecholamines; cocaine; cytokine; drug administration rate /duration; electrocardiography; endotoxins; enzyme linked immunosorbent assay; gene expression; hematology; hemodynamics; inflammation; interleukin 1; laboratory rat; lipopolysaccharides; neuroregulation; northern blottings; receptor sensitivity; septic shock; substance abuse related disorder; sympathetic nervous system; tumor necrosis factor alpha; ultrasound blood flow measurement; vascular resistance

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.

描述：对内毒素血症的宿主防御反应在个人方面有所不同。可卡因 使用进一步损害对某些人类微生物感染的反应， 尽管导致个体易感性休克的因素 在药物滥用的背景下，尤其复杂且理解不佳。它 似乎多个因素相互作用以确定个人响应能力 包括对急性炎症反应的自主性调节。这 提案基于可卡因将增强易感性的前提 对于某些人而言，在某些人中更容易震惊。我们提出了这一点 对可卡因的发散血管反应性在 诱导心血管功能障碍，包括败血性休克综合征 来自革兰氏阴性传染剂。交感神经的影响， 可卡因可能在心血管疾病中均存在 病原体诱导的细胞因子基因表达，从而降低了生存率 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 在有意识的大鼠中，可卡因唤起了全身血管的大量增加 抗性（SYSVR）和肾脏sysmpathetic神经活动与 指定血管反应者的动物中心输出量（CO）的减少。在 对比度，混合响应者的SYSVR增加较小，CO的增加。 我们的证据表明血管和混合响应者之间的差异 取决于CNS介导的对可卡因的交感神经反应。我们 假设对可卡因和可卡因和 血管反应者中指出的内毒素血症会导致威胁生命的休克 要么更大的受体灵敏度丧失或增强的表达 促炎性细胞因子。该提议将揭示变更的原因 急性和慢性可卡因使用后内毒素血症的预后。首先，我们 将验证急性可卡因预处理会差异影响 暴露于大鼠的心血管反应，细胞因子表达和致死性 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制模型。第二，我们将确定 外周肾上腺素能受体和交感神经的贡献 负责个人敏感性变化的系统 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 特定外周自闭症在介导可变的血流动力学和 细胞因子对LP的反应。我们将评估促炎性细胞因子合成 以及血浆，肝，脾和肺的水平，并阻止 IL-1B和TNF-alpha。第四，我们将研究长期暴露于 可卡因在自主调节模式和细胞因子表达急性的模式上 内毒素血症。最后，我们将研究自主教和 对暴露于大鼠的内毒素血症的易感性的细胞因子反应性 重复可卡因。这些研究将为您提供新的见解 与感染相关期间心血管功能障碍的发病机理 炎症并阐明交感神经系统在 调节血管张力和细胞因子反应性。这些信息将 有助于我们理解诱发因素的发生率和 人类败血性休克的严重程度以及可卡因使用的机制 影响这个过程。