Molecular Control of Gut Permeability in Trauma

创伤中肠道通透性的分子控制

• 批准号: 7932507
• 负责人: MACK H WU
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932507
• 关键词: Abdomen; Accidents; Adherens Junction; Adult Respiratory Distress Syndrome; Albumins; American; Animals; Bacteria; Bacterial Translocation; Blood; Blood Volume; Burn Trauma; Burn injury; Cells; Cellular biology; Chemical Burns; Clinical; Compartment syndromes; Coupled; Critical Care; Cultured Cells; Cytoskeleton; Data; Development; Disease; Electrolytes; Endothelial Cells; Endothelium; Epithelial; Epithelial Cells; Epithelium; Evaluation; Extravasation; Failure; Fire - disasters; Functional disorder; Gastrointestinal Surgical Procedures; Glean; Goals; Homeostasis; Hospital Charges; Hypovolemia; Inflammation; Inflammatory; Injury; Intercellular Fluid; Intercellular Junctions; Intervention; Intestines; Ischemia; Lactulose; Lamina Propria; Length of Stay; Leukocytes; Life; Liquid substance; Mannitol; Measurement; Measures; Mediating; Mediator of activation protein; Medical; Mesentery; Microcirculation; Microvascular Permeability; Modeling; Modification; Molecular; Molecular Genetics; Molecular Structure; Morbidity - disease rate; Morphology; Mucous Membrane; Multiple Organ Failure; Myosin Light Chain Kinase; Neutrophil Infiltration; Nutrient; Operative Surgical Procedures; Organ; Pathogenesis; Pathologic Processes; Pathway interactions; Patients; Permeability; Phosphotransferases; Physiological; Plasma; Play; Property; Protein Isoforms; Regulation; Reperfusion Therapy; Research; Research Design; Resolution; Role; Sepsis; Sepsis Syndrome; Severities; Site; Soldier; Surface; Techniques; Testing; Tight Junctions; Time; Tissues; Toxin; Trauma; Veterans; Work; abstracting; base; cadherin 5; clinically relevant; combat; design; effective therapy; fluorescence imaging; gastrointestinal; genetic manipulation; heat injury; improved; in vitro Model; in vivo; insight; intravital microscopy; mortality; mouse model; non-muscle myosin; research study; response; solute; wound

DESCRIPTION (provided by applicant): Abstract Trauma-induced inflammation and multiple organ failure are a major cause of mortality and morbidity in American soldiers and veterans. Gut barrier dysfunction plays a critical role in the development of posttraumatic complications by providing the major site for plasma leakage and bacterial translocation. The intestinal permeability response to burns, a major form of trauma, has not been well characterized, and its cellular and molecular mechanisms remain poorly understood. The goal of this study is to elucidate the cell-specific mechanisms of leaky guts during thermal injury. We propose to characterize the molecular basis of burn-induced hyperpermeability in the intestinal microvascular endothelium and mucosal epithelium. The hypothesis to be tested is that inflammation in the intestinal microcirculation induces endothelial paracellular leakage and neutrophil infiltration into lamina propria leading to mucosal barrier failure. The underlying mechanism involves dynamic remodeling of cell-cell junctions coupled with cytoskeleton contraction triggered by nmMLCK, the non-muscle myosin light chain kinase expressed in endothelial and epithelial cells. The specific aims developed in this proposal are: 1) to characterize the pathophysiology of gut barrier regulation in thermal injury, and 2) to elucidate the molecular mechanisms of gut hyperpermeability. The study design employs complimentary in vivo, ex vivo, and in vitro models that incorporate molecular and genetic approaches into physiological experiments under clinically relevant trauma conditions. A unique aspect of the proposal is that it provides an in-depth evaluation of gut permeability with the ability to discern the endothelial barrier from epithelial barrier function. The significance of this study lies in the potential to establish a new molecular pathway in the regulation of tight and adherens junctions. Data derived from this study would contribute to the advancement of gastrointestinal surgery with implications in the development of effective therapies or surgical interventions against gut barrier injury in patients with trauma and burns. PUBLIC HEALTH RELEVANCE: VA Relevance Trauma is a major cause of mortality and morbidity in American soldiers and veterans. As a typical form of trauma, thermal injury results from flame/chemical burns in combat or anti-terrorist actions as well as from non- work related fire or scald accidents. Despite the improved critical care and wound management, posttraumatic complications remain a life-threatening problem that causes extended hospital stay and charges. The gut plays an important role in the development of multiple organ complications following a severe burn. In particular, gut barrier failure contributes to systemic inflammatory syndrome and sepsis by serving as the major site of blood leakage and bacteria translocation. The mechanisms of leaky guts are poorly understood. This study provides a comprehensive evaluation of the cellular and molecular pathways leading to intestinal hyperpermeability during burn-induced inflammation. The research work has potential impact on the development of surgical or medical interventions against gut barrier injury in VA patients with trauma or inflammatory diseases.

描述（由申请人提供）： 抽象创伤引起的炎症和多器官衰竭是美国士兵和退伍军人死亡和发病率的主要原因。肠道屏障功能障碍通过为血浆泄漏和细菌易位的主要部位提供了创伤后并发症的发展起着至关重要的作用。肠道渗透性对烧伤的反应是一种主要的创伤形式，尚未得到很好的特征，其细胞和分子机制仍然很少了解。这项研究的目的是阐明热损伤过程中渗漏的细胞特异性机制。我们建议表征肠道微血管内皮和粘膜上皮中烧伤诱导的高透明性的分子基础。要检验的假设是，肠道微循环中的炎症会诱导内皮细胞细胞泄漏和中性粒细胞浸润到固有层中，从而导致粘膜屏障衰竭。潜在的机制涉及对细胞 - 细胞连接的动态重塑，并与NMMLCK触发的细胞骨架收缩相结合，NMMLCK触发的非肌肉肌球蛋白轻链激酶在内皮和上皮细胞中表达。该提案中开发的具体目的是：1）表征热损伤中肠道屏障调节的病理生理学，以及2）阐明肠道过敏性的分子机制。该研究设计采用了体内，体内和体外模型的补充，将分子和遗传方法纳入临床相关的创伤条件下的生理实验中。该提案的一个独特方面是，它可以深入评估肠道渗透性，并能够辨别出内皮屏障与上皮屏障功能的能力。这项研究的重要性在于在调节紧密和粘附连接的调节中建立新的分子途径的潜力。从这项研究中得出的数据将有助于胃肠道手术的进步，对创伤和烧伤患者的有效疗法或针对肠道屏障损伤的有效疗法或手术干预的影响。 公共卫生相关性： VA相关性创伤是美国士兵和退伍军人死亡和发病率的主要原因。作为创伤的一种典型形式，热损伤是由于战斗或反恐行为以及非工作相关的火灾或爆炸事故而导致的火焰/化学烧伤造成的。尽管重症监护和伤口管理得到了改善，但创伤后并发症仍然是威胁生命的问题，导致住院延长和指控。严重燃烧后，肠道在多器官并发症的发展中起着重要作用。特别是，肠道屏障衰竭通过作为血液泄漏和细菌易位的主要部位而导致全身性炎症综合征和败血症。漏水的机制知之甚少。这项研究提供了对导致燃烧引起的炎症过程中导致肠道高透明性的细胞和分子途径的全面评估。该研究工作可能会影响VA患有创伤或炎症性疾病的VA患者的外科手术或医疗干预措施的发展。