INTESTINAL INFLAMMATORY SYNERGY BETWEEN HEMORRHAGIC SHOCK AND TRAUMA

毫无疑问，肠道在机体对失血性休克的反应以及随后发生的肠梗阻、全身炎症反应综合征(SIRS)和多器官功能障碍综合征(MODS)的病理生理学中发挥了重要作用。我们和其他人主要通过使用简单的仅出血模型，通常被称为Weigert模型，为理解失血性休克对人体的分子后果做出了贡献。尽管该模型在力学上有价值，但可能不能充分代表临床情况，因此，可能会严重限制对经常出现创伤性失血性休克(T-HS)的受伤患者的治疗结论和治疗洞察力。当然，创伤-失血性休克联合模型呈现了一个更复杂的实验范式，然而，我们的初步数据和现有文献引导我们 假设创伤失血性休克触发了分子和功能事件的协同、可定义的炎症情景，这显著地促进了这一毁灭性临床问题的复杂后遗症。这项建议旨在机械地调查并建立连接特定事件的数据的逻辑线索，这对于理解创伤和出血联合损伤的有害协同作用具有开创性意义。我们认为失血性休克可迅速激活转录因子早期基因反应-1(Egr-1)，该转录因子在上调CD44转录活性中起关键作用。CD44(糖蛋白膜受体)的表达显著增强 细胞外基质(ECM)及其配体(碎裂的透明质酸)从创伤组织中释放出来，协同触发一系列炎症事件，参与导致大量肠源性炎症介质(IL-1β、IL-6、TNF-α、MCP-1、iNOS、COX-2、MMPs)的产生，粘膜屏障功能崩溃(INOS)和肠梗阻(iNOS和COX-2)与管腔有毒产品的泄漏。我们推测这些事件是肠炎症、SIRS和MODS发生的关键。

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.