INTESTINAL INFLAMMATORY SYNERGY BETWEEN HEMORRHAGIC SHOCK AND TRAUMA

失血性休克和创伤之间的肠道炎症协同作用

• 批准号: 6829218
• 负责人: ANTHONY J BAUER
• 金额: $ 21.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6829218
• 关键词: CD44 molecule; biological signal transduction; electrostimulus; enzyme activity; enzyme linked immunosorbent assay; extracellular matrix; gastrointestinal motility /pressure; gastrointestinal system; gene targeting; genetically modified animals; hemorrhagic shock; inflammation; injury; intestinal mucosa; laboratory mouse; multiple organ failure; nitric oxide synthase; receptor expression; regulatory gene; resuscitation; stress; transcription factor; trauma

There is little doubt that the gut plays a seminal role in the pathophysiology of the body's response to hemorrhagic shock and the subsequent development of ileus, the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). We and others have contributed to understanding the molecular consequences of hemorrhagic shock to the body by primarily using a simple hemorrhage only model, commonly referred to as the Weigert model. Although mechanistically valuable, this model may not adequately represent the clinical situation, and, therefore, may seriously limit conclusions and therapeutic insight into the treatment of injured patients, which frequently present with traumatic-hemorrhagic shock (T-HS). Certainly a combined trauma-hemorrhagic shock model presents a more experimentally complicated paradigm, however, our preliminary data and the existing literature has led us to hypothesize that traumatic-hemorrhagic shock triggers a synergistic, definable inflammatory scenario of molecular and functional events that significantly contributes to the complex sequelae of this devastating clinical problem. This proposal is designed to mechanistically investigate and establish a logical thread of data connecting specific events, which are seminal to understanding the detrimental synergy of the combined injuries of trauma and hemorrhage. We propose that hemorrhagic shock rapidly activates the transcription factor early gene response-1 (Egr-1), which is know to play a key role in upregulating CD44 transcriptional activity. The greatly enhanced expression of CD44 (the glycoprotein membrane receptor for extracellular matrix (ECM) products) and the release of its ligands (fragmented hyaluronic acid) from traumatize tissue results in the synergistic triggering of an inflammatory cascade of events, which participates in causing the generation of copious amounts of gut-derived inflammatory mediators (IL-lbeta, IL-6, TNF-alpha, MCP-1, iNOS, COX-2, MMPs), mucosal barrier function breakdown (iNOS) and ileus (iNOS and COX-2) with the leakage of luminal toxic products. We hypothesize that these events are key to the development of intestinal inflammation, SIRS and MODS.

毫无疑问，肠道在机体对失血性休克的反应的病理生理学中起着重要作用，并且随后发生肠梗阻、全身炎症反应综合征（SIRS）和多器官功能障碍综合征（MODS）。我们和其他人通过主要使用简单的出血模型（通常称为Weigert模型），为理解出血性休克对机体的分子后果做出了贡献。虽然在机械上有价值，但该模型可能无法充分代表临床情况，因此，可能严重限制对受伤患者治疗的结论和治疗见解，这些患者经常出现创伤-出血性休克（T-HS）。当然，联合创伤失血性休克模型提供了一个更复杂的实验范例，然而，我们的初步数据和现有文献使我们 假设创伤性失血性休克触发了分子和功能事件的协同的、可定义的炎症情况，其显著促成了这种毁灭性临床问题的复杂后遗症。该建议旨在机械地调查和建立连接特定事件的数据逻辑线索，这对于理解创伤和出血的组合损伤的有害协同作用是至关重要的。我们认为，失血性休克迅速激活转录因子早期基因反应-1（Egr-1），这是已知的上调CD 44转录活性发挥关键作用。CD 44（糖蛋白膜受体）的表达大大增强， 细胞外基质（ECM）产物）及其配体的释放创伤组织中的透明质酸（片段化的透明质酸）导致炎症级联反应的协同触发，其参与引起大量肠源性炎症介质的产生（IL-1 β、IL-6、TNF-α、MCP-1、iNOS、考克斯-2、MMPs）、粘膜屏障功能破坏（iNOS）和肠梗阻（iNOS和考克斯-2）以及管腔毒性产物的渗漏。我们假设这些事件是肠道炎症、SIRS和MODS发展的关键。