Mesenteric Lymph Linking Gut & Distant Organ Injury

连接肠道的肠系膜淋巴

• 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
• 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

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岁以下人群的主要死因，多器官功能障碍综合征是主要死因 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在这个国家具有重大的健康重要性。其中一个主要假设是 创伤后脓毒症和MODS的肠道假说是研究创伤后脓毒症和MODS发生的主要原因。 此外，最近的实验和临床信息表明，对损伤和败血症的反应可能 在男性和女性之间存在差异。因此，这笔赠款的总体假设是创伤 失血性(T/HS)休克所致早期远隔器官损伤和细胞功能障碍继发于肠道 损伤，主要是由通过肠系膜淋巴管离开肠道的因素介导的。我们的次要 主要的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的初步研究的支持，这些研究表明T/HSs诱导了 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)，RED 雄性大鼠的血细胞功能障碍(MchiedoI项目)和骨髓衰竭(Kaiser项目)主要是由 肠系膜淋巴中排出肠道的因子。此外，我们的研究表明，发情前期的雌性大鼠 抵抗这些T/HS诱导的损伤。基于这些结果表明雌性大鼠更耐受 与雄性大鼠相比，性别和性激素调节对T/HS大鼠细胞和器官功能障碍的影响 将会被调查。在所有项目中，T/HS导致这些变化的机制将是 学习。由于T/HS诱导的肠道损伤似乎是引发这一连串事件的初始损伤， Deitch的项目和Feinman的项目都将专注于确定T/HS导致肠道损伤的机制。 此外，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(Mchiedo项目)。总而言之，这些项目将提供 洞察T/HS易患MODS的早期机制，并将澄清性别的作用 性激素作为这一反应的调节器。行政核心将负责协调 各种项目的活动以及成为信息纽带，而动物模型核心将 确保正在使用的模型的一致性，并促进将所获得的结果以及 降低整体提案的成本。人类核心也将有助于促进翻译研究 帮助将人类和动物研究的结果联系起来。最后，Kaiser关注因素的项目 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、红细胞和骨髓功能的这些变化。