GASTRIC DYSFUNCTION AFTER SHOCK: THERAPEUTIC STRATEGIES

休克导致创伤患者不成比例的内脏血管收缩，尽管进行了适当的容量复苏，这种收缩仍然存在。通常，这些患者需要麻醉药或镇静来支持他们在ICU的通气，并需要镇痛药来控制疼痛。通常，肠道功能障碍是由于细胞毒性和炎症介质的激活，通过改变促炎性和抗炎基因产物的表达。然而，我们对激活的分子程序的理解仍然存在重大差距，这些分子程序反过来协调这些有害基因的表达模式、时间和强度。我们的观点是，目前ICU中使用的一些药物通过改变分子信号事件来放大肠道功能障碍，这些信号事件影响了导致肠道损伤和多器官功能障碍综合征的有害和保护基因的表达。PROJECT假说认为，休克通过改变分子应激反应因子引起胃功能障碍，而这些改变可以通过治疗调节。目前的研究计划将表征这些分子信号事件，并确定决定休克后胃损伤命运的基因产物，以制定可能改善ICU环境下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。第一个目标是描述休克后胃中发生的分子事件。第二个目标将描述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。第三个目的是研究环加氧酶抑制剂和其他镇痛药对休克性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导致潜在的治疗药物，通过减少对昂贵的应激性胃炎预防药物的需求，消除休克后的胃功能障碍，允许胃喂养继续进行，并减少ICU的住院时间和ICU死亡率。

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.