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: 5212115
• 负责人: FRANK G MOODY
• 金额: --
• 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/5212115
• 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： 肠道是多系统器官的始作俑者和受害者 失败（MOF）。 两大目标 - 进一步明确 肠瘀在 MOF 发病机制中的作用，并确定 导致肠道蠕动改变的机制 因应激源而导致肠道停滞 胰腺炎、腹膜炎和内毒素血症将通过以下方式完成：1) 将完整动物肠道蠕动的变化与 MOF 相关的后遗症； 2) 确定是预防还是逆转 肠瘀会减少后遗症； 3）确定因素 损害肠壁屏障功能（上皮、血管和 免疫学）增强由抑郁的压力源引起的后遗症 肠道蠕动； 4) 识别生化和分子变化 在肠道平滑肌中，这可能是收缩力变化的原因；和 5）评估选定的神经分泌和旁分泌在 肠道蠕动的变化。 老鼠和负鼠将被检测 带有用于测量胆囊排空和肠道的导管 过境。 对肠内内容物进行取样以进行定量细菌学分析。 电极将被放入胆道括约肌（仅限负鼠）并 每隔一段时间检查肠道肌肉以监测迁移 肌电复合体。 肠道运输和肌电活动将 与肠道细菌过度生长、细菌 易位至淋巴结和远处器官，以及肝功能 控制和压力后。 动力在诱发这些方面的作用 后遗症将通过扭转预期的运动抑制来测试 使用促运动药物并结合改变运动性的压力源 项目 2、3 和 4 中发现的改变障碍的压力源 肠道的功能。 外在神经和内在神经的作用 将使用以下试剂对完整动物进行药理学研究： 阻断肾上腺素能活性和一氧化氮（NO）的产生。 精神错乱 通过评估收缩性、钙 ATP 酶、 肌球蛋白轻链激酶活性和收缩蛋白的变化 内容物、亚型以及编码特定亚型的 mRNA。 通过评估 NO 来评估旁分泌和神经分泌的参与 合酶活性和编码组成型和 酶的诱导形式，通过确定是否有拮抗剂 酶将通过监测变化来改变压力源的影响 IL-1、IL-6 和 TNF 以及编码这些物质的 mRNA 的表达 细胞因子，并通过确定特定细胞因子的拮抗剂是否会 改变压力源的影响。 这些实验的数据可能 为制定预防、改善和/或 扭转 MOF 的致命后果。