GASTRIC DYSFUNCTION AFTER SHOCK: THERAPEUTIC STRATEGIES

休克后胃功能障碍：治疗策略

• 批准号: 6813357
• 负责人: DAVID W MERCER
• 金额: $ 14.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-06 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6813357
• 关键词: anesthetics; biological signal transduction; drug screening /evaluation; gastrointestinal disorder; gastrointestinal disorder chemotherapy; genetic regulation; immunogenetics; immunoregulation; laboratory rat; molecular pathology; morphine; nonhuman therapy evaluation; prostaglandin endoperoxide synthase; shock; stress; stress proteins

Shock causes disproportionate splanchnic vasoconstriction in trauma patients that persists despite adequate volume resuscitation. Typically, these patients require anesthetics or sedation for their ventitatory support in the ICU and analgesics for pain control. Frequently, gut dysfunction results due to activation of cytotoxic and inflammatory mediators through changes in expression of pro and anti-inflammatory gene products. However, we still have significant gaps in our understanding of the molecular programs activated that in turn orchestrate the pattern, timing, and magnitude of expression of these injurious genes. It is our contention that some of the currently used agents in the ICU amplify gut dysfunction through changes in molecular signalling events that influence the expression of injurious and protective genes that contribute to gut injury and multiple organ dysfunction syndrome. It is the PROJECT HYPOTHESIS that shock causes gastric dysfunction through changes in molecular stress response factors and that these changes can be therapeutically modulated. The current research proposal will characterize these molecular signalling events and identify the gene products that determine the fate of the injured stomach following shock to develop potential therapeutic strategies that may improve gastric function in the ICU setting. The specific aims to prove or disprove this hypothesis are as follows. The first aim will characterize the molecular events that occur in the stomach following shock. The second aim will characterize the effects of the anesthetic ketamine as well as other anesthetics and sedatives on shock induced gastric dysfunction and molecular stress response genes. The third aim will examine the effects of cyclo-oxygenase inhibition and other analgesics on shock induced gastric dysfunction and molecular stress response genes. The results of the proposed studies could result in potential therapeutic agents that would abrogate gastric dysfunction following shock with a resultant decrease in the need for expensive stress gastritis prophylactic agents, allow for gastric feeding to proceed unabated, and reduce ICU length of stay and ICU mortality.

休克导致创伤患者内脏血管不成比例收缩，即使进行了充分的容量复苏，这种收缩仍持续存在。通常，这些患者需要麻醉剂或镇静剂用于ICU中的通气支持，并需要镇痛剂用于疼痛控制。通常，肠道功能障碍的结果是由于细胞毒性和炎症介质通过促炎和抗炎基因产物表达的变化而激活。然而，我们在理解激活的分子程序方面仍然存在重大差距，这些分子程序反过来又协调了这些有害基因表达的模式，时间和幅度。我们的论点是，目前在ICU中使用的一些药物通过改变分子信号传导事件来放大肠道功能障碍，这些分子信号传导事件影响导致肠道损伤和多器官功能障碍综合征的损伤性和保护性基因的表达。该项目假设休克通过分子应激反应因子的变化引起胃功能障碍，并且这些变化可以通过治疗调节。目前的研究计划将描述这些分子信号事件，并确定决定休克后胃损伤命运的基因产物，以开发可能改善ICU环境中胃功能的潜在治疗策略。证明或反驳这一假设的具体目的如下。第一个目标将描述休克后胃中发生的分子事件。第二个目标将表征麻醉剂氯胺酮以及其他麻醉剂和镇静剂对休克诱导的胃功能障碍和分子应激反应基因的影响。第三个目标是研究环氧合酶抑制剂和其他镇痛剂对休克诱导的胃功能障碍和分子应激反应基因的影响。拟议研究的结果可能会产生潜在的治疗药物，这些药物将消除休克后的胃功能障碍，从而减少对昂贵的应激性胃炎预防药物的需求，允许胃饲持续进行，并减少ICU住院时间和ICU死亡率。