Mesenteric Lymph Linking Gut & Distant Organ Injury

连接肠道的肠系膜淋巴

• 批准号: 7900892
• 负责人: EDWIN A DEITCH
• 金额: $ 160.97万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900892
• 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岁以下人群死亡的主要原因，MODS是重症监护病房死亡的主要原因。因此，了解创伤失血性休克（T/HS）导致MODS的机制在这个国家具有重要的健康意义。解释创伤后脓毒症和MODS发展的主要假说之一是MODS的肠道假说。 此外，最近的实验和临床信息表明，男性和女性对损伤和脓毒症的反应可能不同。因此，本研究的总体假设是创伤出血性（T/HS）休克诱导的早期远端器官损伤和细胞功能障碍继发于肠道损伤，主要由通过肠系膜血管离开肠道的因子介导。我们的第二个主要假设是性别和性激素调节T/HS后的肠道和远端器官和细胞功能障碍。我们的初步研究支持了这些假设，表明雄性大鼠中T/HS诱导的肺损伤和内皮细胞活化/功能障碍（Deitch项目）、中性粒细胞活化（豪瑟项目）、红细胞功能障碍（MachiedoI项目）和骨髓衰竭（Kaiser项目）主要由肠系膜淋巴中的肠道因子介导。此外，我们的研究表明，发情前期雌性大鼠对这些T/HS诱导的损伤具有抵抗力。基于这些结果表明雌性大鼠比雄性大鼠对T/HS更具抗性，将研究性别和性激素调节对细胞和器官功能障碍的影响。在所有项目中，将研究T/HS导致这些变化的机制。由于T/HS诱导的肠道损伤似乎是引发这一系列事件的起始损伤，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，还将在创伤患者中开展重点人体研究，调查创伤诱导的中性粒细胞活化（豪瑟项目）和RBC功能障碍（Machiedo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，并将澄清性别和性激素作为这种反应的调节剂的作用。行政核心将协调各个项目的活动，并成为信息纽带，而动物模型核心将确保所使用模型的一致性，促进所获得结果的整合，并降低整体提案的成本。人类核心将有助于促进转化研究，并有助于将人类和动物研究的结果相关联。最后，Kaiser专注于因子分离的项目已被纳入，以回答T/HS肠系膜淋巴中存在哪些因子导致中性粒细胞，RBC和骨髓功能的这些变化。

项目成果

Recombinant factor XIII diminishes multiple organ dysfunction in rats caused by gut ischemia-reperfusion injury.

重组因子 XIII 可减轻大鼠肠道缺血再灌注损伤引起的多器官功能障碍。

• DOI: 10.1097/shk.0b013e31818bbe21
• 发表时间: 2009
• 期刊: Shock (Augusta, Ga.)
• 作者: Zaets,SergeyB;Xu,Da-Zhong;Lu,Qi;Feketova,Eleonora;Berezina,TamaraL;Gruda,Maryann;Malinina,IngaV;Deitch,EdwinA;Olsen,EvaHN
• 通讯作者: Olsen,EvaHN

Elimination of C5aR prevents intestinal mucosal damage and attenuates neutrophil infiltration in local and remote organs.

• DOI: 10.1097/shk.0b013e318188b3cc
• 发表时间: 2009-05
• 期刊: Shock (Augusta, Ga.)
• 作者: Xu DZ;Zaets SB;Chen R;Lu Q;Rajan H;Yang X;Zhang J;Feketova E;Bogdan N;Deitch EA;Cao Y
• 通讯作者: Cao Y

Gender differences in glucose variability after severe trauma.

严重创伤后血糖变异性存在性别差异。

• 发表时间: 2010
• 期刊: The American surgeon
• 作者: Mohr,AliciaM;Lavery,RobertF;Sifri,ZiadC;Anjaria,DevashishJ;Koernig,Robert;Deitch,EdwinA;Livingston,DavidH
• 通讯作者: Livingston,DavidH