Substance P-Mediated Cardiovascular Inflammation

描述(由申请人提供)：本提案涉及神经源性多肽，特别是P物质(SP)引起的心脏炎症的病理生物学。最近的数据支持神经元NMDA受体在镁缺乏(MGD)引起的心血管炎症过程中所起的作用。此外，并发肠炎可能通过激活中性粒细胞和内毒素信号而加重心肌病的晚期。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。目的2.检测MGD时循环和心肌组织中NK-1受体的表达和促炎/氧化反应的程度。目的3.(与Shea-Donohue博士)评估MGD是否在肠道引起神经源性炎症，这与肠道功能改变、粘膜屏障通透性增强和对氧化应激的敏感性增加有关；评估全身炎症反应综合征(SIRS)或内毒素血症是否显著导致“远距离的心脏炎症/心肌病”。目的4.评估在MGD反应后期是否出现灌流大鼠头的基础收缩功能缺陷，以及体内干预措施(MK-801、NK-1受体阻滞剂、RTX、磷酰胺、抗生素)是否对心脏基础收缩功能障碍和对LTR应激的耐受性有显著影响。目的5.评估MGD对内毒素抵抗和敏感小鼠的促炎作用是否发生改变。我们将使用免疫组织化学和分子/蛋白质生物学(RT-PCR，Western-blotting)技术和基因芯片技术相结合的方法来评估相关的基因表达；也将使用更传统的生化方法(组织谷胱甘肽和抗氧化剂状态，血浆异丙烷水平)和生物物理学方法(ESR-自旋捕获自由基和隔离灌流的头部中的NO)。图1概述了研究计划中要追求的假设。临床MGD与心力衰竭和其他疾病过程中的促炎事件的潜在相关性在正文中进行了阐述。

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.