Substance P-Mediated Cardiovascular Inflammation

描述（由申请人提供）：本提案阐述了神经源性肽，特别是P物质（SP）引起的心脏炎症的病理生物学。 最近的数据提供了支持的神经元NMDA受体的心血管炎症过程中的贡献，由于镁缺乏症（MgD）。 此外，并发的肠道炎症可能通过激活中性粒细胞和内毒素信号而增强心肌病的晚期。 这些最新发现为以下目标和合作提供了基础：目标1。 评估NMDA受体激活对早期SP升高的贡献，以及在饮食MgD的急性“触发阶段”如何调节SP。 目标2. 确定MgD期间循环和心脏组织中NK-1受体表达和促炎/氧化反应的程度。 目标3. (with Shea-Donohue博士）评估MgD是否在肠道中诱导神经源性炎症，其与改变的肠功能、增强的粘膜屏障通透性和对氧化应激的敏感性增加相关;评估全身炎症反应综合征（SIRS）或内毒素血症是否显著促进“远处心脏炎症/心肌病”。“目标4。 评估在MgD的晚期反应阶段期间灌注大鼠头部的基线收缩性是否存在缺陷，以及体内干预（MK-801、NK-1受体阻滞剂、RTX、磷酰胺、抗生素）是否对心脏基线收缩性功能障碍和对ltR应激的耐受性具有显著影响。 目标5。 评估MgD的促炎作用是否在LPS抗性小鼠与敏感小鼠中改变。 我们将采用免疫组织化学和分子/蛋白质生物学的结合（RT-PCR、Western-blotting）技术和基因芯片技术来评估相关的基因表达;更传统的生物化学（组织谷胱甘肽和抗氧化状态，血浆异丙烷水平）和生物物理（ESR-自旋捕获分离灌注头中的自由基和NO）研究计划中的假设在图1中概述。 潜在的相关性，临床MgD的促炎事件，心力衰竭和其他疾病的过程中解决的文本。

DESCRIPTION (provided by applicant): This proposal addresses the pathobiology of inflammation of the heart due to neurogenic peptides, particularly substance P (SP). Recent data have provided support for the neuronal NMDA receptor contribution to the cardiovascular inflammatory process due to Mg-deficiency (MgD). In addition concurrent intestinal inflammation may enhance the later phase of the cardiomyopathy via activation of PMNs and endotoxin signaling. These recent findings provide the basis for the following Aims and collaborations: Aim 1. Assess the contribution of NMDA-receptor activation to the early SP elevation and how SP can be modulated during the acute "trigger phase" of dietary MgD. Aim 2. Determine the extent of NK-1 receptor expression and proinflammatory/oxidative response in the circulation and cardiac tissues during MgD. Aim 3. (with Dr. Shea-Donohue) Assess if MgD induces a neurogenic inflammation in the gut that is associated with altered intestinal function, enhanced mucosa barrier permeability, and increased sensitivity to oxidative stress; assess if systemic inflammatory response syndrome (SIRS) or endotoxemia contribute significantly to "cardiac inflammation/cardiomyopathy at a distance." Aim 4. Assess whether defects in baseline contractility of perfused rat heads develops during the late response phase of MgD and if in vivo interventions (MK-801, NK-1 receptor blocker, RTX, phosphoramidon, antibiotics) have a significant impact on cardiac baseline contractility dysfunction and tolerance to ltR stress. Aim 5. Assess if proinflammatory effects of MgD are altered in LPS-resistant vs. sensitive mice. We will employ a combination of immunohistochemical and molecular/protein biology (RT-PCR, Western-blotting) techniques, and gene chip technology to assess relevant genetic expression; more traditional biochemical (tissue glutathione and antioxidant status, plasma isoprotane level) and biophysical (ESR-spin trapping of free radicals and NO in isolated perfused heads) approaches will also be used.The hypotheses to be pursued in the Research Plan are outlined in Illustration 1. The potential relevance of clinical MgD to proinflammatory events in heart failure and other disease processes is addressed in the text.