PATHOGENESIS OF MULTIPLE ORGAN FAILURE

随着区域性创伤系统的成熟和早期干预措施的改进，原本会死亡的重伤患者现在存活了下来，但发生多器官衰竭(MOF)的风险很高。随着重症监护病房(ICU)治疗的进步，MOF的死亡率正在下降，但它仍然是导致ICU晚期死亡和住院时间延长的主要原因。多器官功能衰竭是由功能失调的炎症反应引起的。胃肠道既是这种反应的煽动者，也是受害者，由此导致的肠道功能障碍导致持续的多器官功能衰竭。一个由基础和临床科学家组成的多学科团队将继续在失血性休克、缺血/再灌注(I/R)和脓毒症的实验室模型中表征肠道损伤和功能障碍。在这个资金周期中，他们将检验这样一个假设，即治疗干预可以调节危重损伤患者的肠道炎症和由此导致的肠道功能障碍，以改善结果。为了取得有意义的进展更好地理解分子事件 需要调节肠道炎症的药物。因此，我们将描述肠系膜I/R后激活促炎和抗炎的细胞特异性分子程序，并研究不同的保护性干预措施(缺血预适应、低温、α-黑素细胞刺激素)如何调节这些程序，以确定限制肠道损伤和/或加速其修复的共同途径。复苏是拯救生命的强制性干预措施。这个 目前的护理标准是早期容量负荷等渗晶(主要是乳酸林格氏)和输血，以限制缺血性损伤的严重程度。对于严重休克，这种方法可以通过修改它来减少医源性肠道水肿，并通过改变它来专门控制肠I/R引起的炎症。因此，我们将通过标准护理标准的等渗晶体复苏来研究引起有问题的肠水肿的因素，以及不断增加的水肿如何影响重要的肠道功能。我们将重点关注如何选择 复苏策略(含或不含胶体的高渗盐水)对肠道I/R引起的炎症反应有良好的调节作用。 肠内营养(EN)是改善患者预后的另一个重要护理方面。不幸的是，胃损伤和功能障碍削弱了对高危患者进行肠道喂养的能力，并迫使人们使用昂贵且可能有害的预防应激性胃炎的药物。我们将研究复苏、镇静和止痛药如何改变胃内的炎症反应，以限制粘膜损伤和改善胃排空。 我们将研究新的腔内干预措施如何改善胃和回肠的炎症，以保护屏障功能。来自这些项目的知识将允许修改常规护理以促进胃喂养，并扩大EN的定义，以包括腔内制剂，其作用是限制肠道炎症和功能障碍，以增强EN耐受性。同时，在我们的人类受试者中，核心实验室观察将 在有重点的观察性研究中进行测试，以确定它们与人类病理生理学的相关性。这些临床观察将反过来改变正在进行的实验室研究的方向，并作为试点和可行性数据，以利用资金进行更大的临床试验。

As regional trauma systems mature and early interventions improve, severely injured patients who would have previously died, now survive but are at high risk for multiple organ failure (MOF). With advances in intensive care unit (ICU) therapy, the mortality of MOF is decreasing, but.it still remains the leading cause of late ICU deaths and prolonged hospital stays. MOF occurs as a result of a dysfunctional inflammatory response. The gastrointestinal tract is both an instigator and a victim of this response, and the resulting gut dysfunctions contribute to ongoing MOF. A multidisciplinary team of basic and clinical scientists will continue to characterize gut injury and dysfunction in laboratory models of hemorrhagic shock, ischemia/reperfusion (I/R), and sepsis. In this funding cycle, they will test the HYPOTHESIS that therapeutic interventions can modulate gut inflammation and resulting gut dysfunction in critically injured patients to improve outcome. To make meaningful advances a better understanding of the molecular events that regulate gut inflammation is needed. We will therefore characterize cell specific molecular programs that activate pro- and anti-inflammation after mesenteric I/R and investigate how these are modulated by different protective interventions (ischemic preconditioning, hypothermia, alpha-melanocyte stimulating hormone) to identify common pathways to limit gut injury and/or hasten its repair. Resuscitation is an obligatory intervention that saves lives. The current standard of care is early volume loading with isotonic crystalloids (principally lactated Ringer's) and blood transfusions to limit the severity of the ischemic insult. For severe shock, this approach could be improved by modifying it to minimize iatrogenic gut edema and by altering it to specifically control gut I/R induced inflammation. We will therefore study the factors that cause problematic bowel edema with standard of care isotonic crystalloid resuscitation and how increasing edema affects vital gut functions. We will focus on how alternative resuscitation strategies (hypertonic saline with or without colloids) can favorably modulate gut I/R induced inflammation. Enteral nutrition (EN) is another important aspect of care that improves patient outcome. Unfortunately, gastric injury and dysfunction impair the ability to enterally feed high risk patients as well as mandate the use of expensive and potentially harmful prophylaxis against stress gastritis. We will study how resuscitation, sedatives, and analgesics can modify the inflammatory response in the stomach to limit mucosal injury and improve gastric emptying. We will study how the novel intraluminal interventions can modify inflammation in the stomach and ileum to preserve barrier function. Knowledge from these projects will allow modification of routine care to facilitate gastric feeding and to expand the definition of EN to include intraluminal agents whose role is to limit gut inflammation and dysfunction to enhance EN tolerance. Simultaneously, in our HUMAN SUBJECTS CORE laboratory observations will be tested in focused observational studies to determine their relevance in human pathophysiology. These clinical observations will in turn redirect ongoing laboratory investigations and serve as pilot and feasibility data to leverage funding for larger clinical trials.