Substance P-Mediated Cardiovascular Inflammation

描述（由申请人提供）：该提案涉及神经源性肽，特别是P物质（SP）引起的心脏炎症的病理生物学。最近的数据支持神经元NMDA受体在镁缺乏（MgD）引起的心血管炎症过程中的作用。此外，并发的肠道炎症可能通过激活pmn和内毒素信号通路来增强心肌病的后期。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，以及如何在膳食MgD的急性“触发阶段”调节SP。目标2。测定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。（与Shea-Donohue博士一起）评估MgD是否诱导肠道神经源性炎症，这种炎症与肠道功能改变、粘膜屏障通透性增强和对氧化应激的敏感性增加有关；评估全身性炎症反应综合征（SIRS）或内毒素血症是否对“远距离心脏炎症/心肌病”有显著影响。目标4。评估在MgD的反应后期，灌注大鼠头部的基线收缩力是否出现缺陷，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力功能障碍和对ltR应激的耐受性有显著影响。目标5。评估MgD的促炎作用在lps抗性小鼠和敏感小鼠中是否发生改变。我们将结合免疫组织化学和分子/蛋白质生物学（RT-PCR, Western-blotting）技术以及基因芯片技术来评估相关的基因表达；更传统的生化方法（组织谷胱甘肽和抗氧化状态，血浆异丙烷水平）和生物物理方法（游离灌注头部自由基和NO的esr自旋捕获）也将被使用。在研究计划中要追求的假设概述在图1中。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文中得到了解决。

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.