Mesenteric Lymph Linking Gut & Distant Organ Injury

连接肠道的肠系膜淋巴

基本信息

批准号：
7250850
负责人：
EDWIN A DEITCH
金额：
$ 152.77万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
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/7250850
关键词：
Mesenteric Lymph Linking Gut Distant

项目摘要

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.

外伤是 40 岁以下人群死亡的主要原因，MODS 是导致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) 导致的 MODS 在这个国家具有重大的健康意义。主要假设之一是为了解释创伤后脓毒症和MODS的发展而进行的研究是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存在差异。因此，这项资助的总体全球假设是创伤出血性（T/HS）休克引起的早期远端器官损伤和细胞功能障碍是继发于肠道的损伤主要由通过肠系膜淋巴管排出肠道的因子介导。我们的中学主要假设是性别和性激素调节肠道，从而调节远处的器官和细胞 T/HS 后功能障碍。这些假设得到了我们初步研究的支持，表明 T/HS 诱导肺损伤和内皮细胞激活/功能障碍（Deitch 项目），中性粒细胞激活（Hauser 项目），红色雄性大鼠的血细胞功能障碍（MachiedoI 项目）和骨髓衰竭（Kaiser 项目）主要由因子通过肠系膜淋巴液排出肠道。此外，我们的研究表明，发情前期的雌性大鼠对这些 T/HS 引起的损伤具有抵抗力。基于这些结果表明雌性大鼠的抵抗力更强性别和性激素调节对细胞和器官功能障碍的影响将被调查。在所有项目中，T/HS 导致这些变化的机制将是研究过。由于 T/HS 诱导的肠道损伤似乎是引发这一级联事件的起始损伤， Deitch 的项目和 Feinman 的项目都将重点确定 T/HS 导致肠道损伤的机制。此外，还将对创伤患者进行重点人体研究，调查创伤引起的中性粒细胞激活（Hauser 项目）和红细胞功能障碍（Machiedo 项目）。总而言之，这些项目将提供深入了解 T/HS 易患 MODS 的早期机制，并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各个项目的活动以及信息纽带，而动物模型核心将确保所使用模型的一致性并促进所获得结果的整合降低整体提案的成本。人类核心也将有助于促进转化研究帮助关联人类和动物研究的结果。最后，Kaiser 的项目重点关注因素分离是为了回答 T/HS 肠系膜淋巴中存在哪些因素的问题导致中性粒细胞、红细胞和骨髓功能发生这些变化。