PATHOGENESIS OF MULTIPLE ORGAN FAILURE

多器官衰竭的发病机制

• 批准号: 7502011
• 负责人: John B Holcomb
• 金额: $ 127.44万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502011
• 关键词: PATHOGENESIS; MULTIPLE; ORGAN; FAILURE

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.

随着区域创伤系统的成熟和早期干预措施的改善，以前可能死亡的严重受伤患者现在存活下来，但多器官功能衰竭（MOF）的风险很高。随着重症监护室（ICU）治疗的进步，MOF的死亡率正在下降，but.it仍然是ICU晚期死亡和住院时间延长的主要原因。MOF的发生是功能失调的炎症反应的结果。胃肠道既是这种反应的发起者，也是受害者，由此产生的肠道功能障碍有助于进行中的MOF。一个由基础和临床科学家组成的多学科团队将继续在出血性休克、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。在这个资助周期中，他们将测试这样一个假设，即治疗干预可以调节危重患者的肠道炎症和由此产生的肠道功能障碍，以改善预后。为了更好地理解分子事件， 来调节肠道炎症。因此，我们将表征在肠系膜I/R后激活促炎症和抗炎的细胞特异性分子程序，并研究这些程序如何通过不同的保护性干预（缺血预处理，低温，α-黑素细胞刺激激素）进行调节，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。的 目前的护理标准是用等渗晶体（主要是乳酸林格氏液）和输血进行早期容量负荷，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以最大限度地减少医源性肠道水肿和通过改变它以特异性控制肠道I/R诱导的炎症来改进。因此，我们将研究标准等渗晶体复苏治疗引起问题性肠水肿的因素，以及水肿增加如何影响重要的肠道功能。我们将重点讨论如何替代 复苏策略（含或不含胶体的高渗盐水）可以有利地调节肠I/R诱导的炎症。 肠内营养（EN）是改善患者预后的另一个重要方面。不幸的是，胃损伤和功能障碍损害了肠内喂养高危患者的能力，并要求使用昂贵且潜在有害的预防应激性胃炎的方法。我们将研究复苏剂、镇静剂和镇痛剂如何改变胃的炎症反应，以限制粘膜损伤和改善胃排空。 我们将研究新的腔内干预如何改变胃和回肠的炎症，以保护屏障功能。从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，包括管腔内药物，其作用是限制肠道炎症和功能障碍，以提高EN耐受性。同时，在我们的人类受试者核心实验室观察中， 在重点观察性研究中进行测试，以确定其在人类病理生理学中的相关性。这些临床观察结果将反过来重新定向正在进行的实验室研究，并作为试点和可行性数据，以利用资金进行更大规模的临床试验。

项目成果

Acute mesenteric ischemia/reperfusion down regulates renal PGE2 synthesis.

急性肠系膜缺血/再灌注下调肾脏 PGE2 合成。

• DOI: 10.1016/0952-3278(95)90095-0
• 发表时间: 1995
• 期刊: Prostaglandins, leukotrienes, and essential fatty acids
• 作者: Myers,SI;Hernandez,RH;Horton,JW
• 通讯作者: Horton,JW

Splanchnic PGI2 release and "no reflow" following intestinal reperfusion.

肠道再灌注后内脏 PGI2 释放且“无回流”。

• DOI: 10.1006/jsre.1995.1088
• 发表时间: 1995
• 期刊: The Journal of surgical research.
• 作者: Turnage,RH;Kadesky,KM;Bartula,L;Guice,KS;Oldham,KT;Myers,SI
• 通讯作者: Myers,SI

Burn injury decreased splanchnic PGI2 release is restored by treatment with lazaroid.

烧伤后内脏 PGI2 释放减少可通过拉齐若得治疗恢复。

• DOI: 10.1016/0090-6980(93)90017-2
• 发表时间: 1993
• 期刊: Prostaglandins
• 作者: Myers,SI;Hernandez,R;White,DJ;Horton,JW
• 通讯作者: Horton,JW

Intestinal migrating myoelectric complexes in rats with acute pancreatitis and bile duct ligation.

急性胰腺炎和胆管结扎大鼠的肠道迁移肌电复合体。

• DOI: 10.1006/jsre.1993.1127
• 发表时间: 1993
• 期刊: The Journal of surgical research
• 作者: Li,YF;Newton,TJ;Weisbrodt,NW;Moody,FG
• 通讯作者: Moody,FG

Poloxamer 188 inhibition of ischemia/reperfusion injury: evidence for a novel anti-adhesive mechanism.

泊洛沙姆 188 抑制缺血/再灌注损伤：新型抗粘连机制的证据。

• 发表时间: 2010
• 期刊: Annals of clinical and laboratory science
• 影响因子: 0.8
• 作者: Hunter,RobertL;Luo,AnnieZ;Zhang,Rongzhen;Kozar,RosemaryA;Moore,FrederickA
• 通讯作者: Moore,FrederickA