GASTROINTESTINAL AND BILIARY MOTILITY IN MULTIPLE ORGAN FAILURE

多器官衰竭时的胃肠道和胆道运动

• 批准号: 3734803
• 负责人: FRANK G MOODY
• 金额: --
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3734803
• 关键词: amine oxidoreductase; bile ducts; blood toxicology; cholestasis; cytochrome P450; disease /disorder model; electromyography; endotoxins; gastrointestinal absorption /transport; gastrointestinal infection; gastrointestinal motility /pressure; gene expression; interleukin 1; interleukin 6; intestine obstruction; laboratory rat; membrane permeability; multiple organ failure; muscle function; nitric oxide; opossums; physiologic stressor; smooth muscle; trauma; tumor necrosis factor alpha

The long-term goal of this research is to test the HYPOTHESIS that the intestine serves as an instigator and a victim of Multisystem Organ Failure (MOF). Two major OBJECTIVES - to further define the role of intestinal stasis in the pathogenesis of MOF, and to determine the mechanisms responsible for the alterations in intestinal motility that lead to intestinal stasis in response to stressors that induce pancreatitis, peritonitis, and endotoxemia will be accomplished by: 1) Correlating changes in intestinal motility in the intact animal with sequelae associated with MOF; 2) Determining if prevention or reversal of intestinal stasis will decrease sequelae; 3) Determining if factors that compromise gut wall barrier functions (epithelial, vascular, and immunologic) enhance sequelae induced by stressors that depress intestinal motility; 4) Identifying the biochemical and molecular changes in gut smooth muscle that may account for changes in contractility; and 5) evaluating the role of selected neurocrines and paracrines in the changes in intestinal motility. Rats and opossums will be instrumented with catheters for measurement of gallbladder emptying and intestinal transit. Enteral contents will be sampled for quantitative bacteriology. Electrodes will be placed into the biliary sphincter (opossum only) and the muscle of the gut at intervals in order to monitor the migrating myoelectric complex. Intestinal transit and myoelectric activity will be correlated with intestinal bacterial overgrowth, bacterial translocation to lymph nodes and distant organ, and liver function during control and after stressors. The role of motility in inducing these sequelae will be tested by reversing the expected depression of motility with prokinetic drugs and by combining stressors that alter motility with stressors that are found in Projects 2, 3, and 4 to alter barrier functions of the gut. The role of extrinsic and intrinsic nerves in intact animals will be investigated pharmacologically using agents that block adrenergic activity and nitric oxide (NO) production. Derangements in muscle will be assessed by evaluating contractility, calcium ATPase, changes in myosin light chain kinase activity, and contractile protein contents, isoforms, and the mRNAs that code for specific isoforms. Paracrine and neurocrine involvement will be assessed by evaluating NO synthase activity and the levels of mRNAs coding for the constitutive and the inducible forms of the enzyme, by determining if antagonists of the enzymes will alter the effects of the stressors, by monitoring changes in the expression of IL-1, IL-6, and TNF and the mRNAs coding for these cytokines, and by determining if antagonists to specific cytokines will alter the effects of the stressors. The data from these experiments may provide a rationale for developing ways to prevent, ameliorate, and/or reverse the lethal outcome of MOF.

这项研究的长期目标是检验以下假设 肠道是煽动者和多系统器官的受害者 失败（MOF）。 两个主要目标 - 进一步定义 MOF的发病机理中的肠道灭绝，并确定 导致肠道运动改变的机制 导致肠停滞，以响应诱导的压力源 胰腺炎，腹膜炎和内毒素血症将通过：1） 将完整动物中肠运动的变化与 与MOF相关的后遗症； 2）确定预防还是逆转 肠停滞会减少后遗症； 3）确定因素是否 损害肠道壁垒功能（上皮，血管和 免疫学增强了抑制压力诱导的后遗症 肠运动； 4）识别生化和分子变化 在肠道平滑肌中，可能会解释收缩力的变化；和 5）评估选定的神经分泌和旁道在 肠运动的变化。 老鼠和负鼠将被仪器 用导管用于测量胆囊排空和肠道 运输。 肠内含量将进行定量细菌学。 电极将被放入胆道括约肌（仅负鼠）和 肠道的肌肉间隔以监视迁移 肌电络合物。 肠道和肌电活动将 与肠道细菌过度生长，细菌相关 在淋巴结和远处的器官和肝功能期间易位 控制和压力后。 运动在诱导这些方面的作用 后遗症将通过逆转预期的运动性抑郁来测试 使用纵向药物，并结合应力源，以改变运动性 在项目2、3和4中发现的压力源以改变障碍 肠的功能。 外在神经和内在神经在 完整的动物将使用药理学研究 阻断肾上腺素能活性和一氧化氮（NO）产生。 扰乱 在肌肉中，将通过评估收缩力评估，钙ATPase， 肌球蛋白轻链激酶活性和收缩蛋白的变化 内容，同工型和MRNA代码为特定的同工型。 旁分泌和神经分泌参与将通过评估NO评估 合成活性和编码本构和编码的mRNA水平和 酶的诱导形式，通过确定是否拮抗剂 酶将通过监视变化来改变应激源的影响 在IL-1，IL-6和TNF的表达中以及编码这些编码的mRNA 细胞因子以及通过确定拮抗剂的特定细胞因子是否会 改变压力源的影响。 这些实验的数据可能 为开发预防，改善和/或 扭转MOF的致命结果。