Mesenteric Lymph Linking Gut & Distant Organ Injury

连接肠道的肠系膜淋巴

• 批准号: 7491780
• 负责人: EDWIN A DEITCH
• 金额: $ 161.2万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7491780
• 关键词: Mesenteric; Lymph; Linking; Gut; Distant

Trauma is the leading cause of death in people under the age of 40 and MODS is the leading cause of death in intensive care units. Consequently, understanding the mechanisms by which trauma-hemorrhagic shock (T/HS) leads to MODS is of major health importance in this country. One of the major hypotheses being studied to explain the development of sepsis and MODS after trauma is the gut hypothesis of MODS. Additionally, there is recent experimental and clinical information that the response to injury and sepsis may differ between males and females. Thus, the overall global hypothesis of this grant is that trauma hemorrhagic (T/HS) shock-induced early distant organ injury and cellular dysfunction is secondary to gut injury and is primarily mediated by factors exiting the gut via the mesenteric lymphatics. Our secondary major hypothesis is that gender and sex hormones modulate gut and hence distant organ and cellular dysfunction after T/HS. These hypotheses are supported by our preliminary studies indicating that T/HSinduced lung injury and endothelial cell activation/dysfunction (Project by Deitch), neutrophil activation (Project by Hauser), red blood cell dysfunction (Project by MachiedoI) and bone marrow failure (Project by Kaiser) in male rats are mediated primarily by factors exiting the gut in the mesenteric lymph. Additionally, our studies show that proestrus female rats are resistant to these T/HS-induced injuries. Based on these results showing that female rats are more resistant to T/HS than male rats, the effects of gender and sex hormone modulation on cellular and organ dysfunction will be investigated. In all of the Projects, the mechanisms by which T/HS leads to these changes will be studied. Since T/HS-induced gut injury appears to be the initiating injury that induces this cascade of events, both Project by Deitch and Project by Feinman, will focus on determining the mechanisms by which T/HS leads to gut injury. Additionally, focused human studies in trauma patients will be carried out investigating trauma-induced neutrophil activation (Project by Hauser) and RBC dysfunction (Project by Machiedo). In summary, these projects will provide insight into the early mechanisms by which T/HS predisposes to MODS and will clarify the roles of gender and sex hormones as modulators of this response. The Administrative Core will serve to coordinate the activities of the various projects as well as be an information nexus, while the Animal Models Core will ensure consistency of the models being used and facilitate integration of the results obtained as well as reduce the costs of the overall proposal. The Human Core will serve to facilitate translational studies as well as aid in correlating the results of the human and animal studies. Lastly, Project by Kaiser focusing on factor isolation has been included to answer the question of what are the factors present in T/HS mesenteric lymph that are causing these changes in neutrophil, RBC and bone marrow function.

创伤是40岁以下的人死亡的主要原因，而mod是死亡的主要原因 在重症监护单元中。因此，了解创伤性造成震动的机制 （T/HS）导致MODS在该国至关重要。主要假设之一是 研究以解释创伤后败血症和mod的发展是mod的肠道假设。 此外，最近还有一些实验和临床信息，即对损伤和败血症的反应可能 男性和女性之间的不同。因此，这笔赠款的总体全球假设是创伤 出血（T/HS）休克引起的早期器官损伤和细胞功能障碍是肠道的继发于肠道的 损伤，主要是由通过肠系膜淋巴管退出肠道的因素介导的。我们的次要 主要假设是性别和性激素调节肠道，因此远处的器官和细胞 T/HS后功能障碍。这些假设得到了我们的初步研究的支持，表明T/HSS诱导 肺损伤和内皮细胞激活/功能障碍（Deitch的项目），中性粒细胞激活（Hauser的项目），红色 雄性大鼠的血细胞功能障碍（Machiedoi的项目）和骨髓衰竭（Kaiser的项目）主要由 退出肠系膜淋巴中肠道的因素。此外，我们的研究表明雌性大鼠是 对这些T/HS诱导的伤害有抵抗力。基于这些结果，表明雌性大鼠更具耐药性 对于T/HS而不是男性大鼠，性别和性激素调节对细胞功能障碍的影响 将被调查。在所有项目中，T/HS导致这些更改的机制将是 研究。由于T/HS引起的肠道损伤似乎是引起这一事件级联的启动伤害，因此 Deitch的项目和Feinman的Project都将专注于确定T/HS导致肠道损伤的机制。 此外，将进行创伤患者的重点人类研究，研究创伤引起的 中性粒细胞激活（Hauser的项目）和RBC功能障碍（Machiedo的项目）。总而言之，这些项目将提供 深入了解T/HS易于模块的早期机制，并将阐明性别的作用 和性激素作为这种反应的调节剂。行政核心将有助于协调 各种项目的活动以及成为信息联系，而动物模型核心将 确保所使用的模型的一致性，并促进获得的结果以及 降低总体建议的成本。人核也将有助于转化研究 有助于将人类和动物研究的结果相关联。最后，Kaiser的项目专注于因素 已经包括隔离以回答T/HS膜淋巴中存在的因素是什么问题 引起中性粒细胞，RBC和骨髓功能的这些变化。