Mesenteric Lymph Linking Gut & Distant Organ Injury

连接肠道的肠系膜淋巴

• 批准号: 7073782
• 负责人: EDWIN A DEITCH
• 金额: $ 159.64万
• 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/7073782
• 关键词: clinical research; hemorrhagic shock; intestines; lymph; mesentery; multiple organ failure; pathologic process; septicemia; trauma

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岁以下人群死亡的主要原因，MODS是死亡的主要原因 在重症监护室因此，了解创伤失血性休克的机制 （T/HS）导致MODS在这个国家具有重要的健康意义。其中一个主要的假设是 研究用来解释创伤后脓毒症和MODS发展的是MODS的肠道假说。 此外，最近的实验和临床信息表明，对损伤和脓毒症的反应可能 男性和女性之间的差异。因此，这项资助的总体全球假设是，创伤 出血性休克（T/HS）诱导早期远端器官损伤和细胞功能障碍是继发于肠 损伤，并且主要由通过肠系膜血管离开肠道的因子介导。我们的次要 一个主要的假设是，性别和性激素调节肠道，从而调节远端器官和细胞， T/HS后功能障碍。我们的初步研究表明，T/HS诱导的 肺损伤和内皮细胞活化/功能障碍（Deitch的项目），中性粒细胞活化（豪瑟的项目），红细胞 雄性大鼠中的血细胞功能障碍（MachiedoI的项目）和骨髓衰竭（Kaiser的项目）主要由 肠系膜淋巴中的肠道因子。此外，我们的研究表明，发情前期雌性大鼠 对这些T/HS诱导的损伤有抵抗力。基于这些结果表明雌性老鼠 与雄性大鼠相比，性别和性激素调节对细胞和器官功能障碍的影响 将进行调查。在所有项目中，T/HS导致这些变化的机制将是 研究了由于T/HS诱导的肠道损伤似乎是诱导这一系列事件的起始损伤， Deitch的项目和Feinman的项目都将集中于确定T/HS导致肠道损伤的机制。 此外，将在创伤患者中进行重点人体研究，调查创伤引起的 中性粒细胞活化（豪瑟的项目）和RBC功能障碍（Machiedo的项目）。总之，这些项目将提供 深入了解T/HS易患MODS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。行政核心将负责协调 活动的各种项目，以及成为一个信息的纽带，而动物模型的核心将 确保所用模型的一致性，并促进所获结果的整合，以及 降低整个提案的成本。人类核心也将有助于促进翻译研究 以帮助将人类和动物研究的结果相关联。最后，凯撒的项目专注于因素 分离已经包括回答T/HS肠系膜淋巴中存在哪些因子的问题 导致中性粒细胞、红细胞和骨髓功能的变化。