THE ROLE OF GENDER ON GUT AND GUT-INDUCED LUNG INJURY

性别对肠道和肠道引起的肺损伤的作用

• 批准号: 7074169
• 负责人: EDWIN A DEITCH
• 金额: $ 8.29万
• 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/7074169
• 关键词: cytoprotection; disease /disorder proneness /risk; estrogens; gastrointestinal circulation; gender difference; hemorrhagic shock; hormone regulation /control mechanism; injury; intestines; ischemia; laboratory rat; lung injury; lymphatic circulation; lymphatic system; membrane permeability; mesentery; nitric oxide synthase; pathologic process; portal vein; septicemia; sex hormones; testosterone; trauma; vascular endothelium

Trauma is the leading cause of death in people under the age of 40 and MODS is the leading cause of death in trauma patients surviving the initial 72 hour injury period. In fact, MODS is the leading cause of death in ICUs today. Although still somewhat controversial, there is recent evidence that the response to injury and sepsis may differ between males and females, with females being more resistant to the adverse consequences of T/HS than males. Thus, understanding the mechanisms by which trauma-hemorrhagic shock (T/HS) leads to MODS, as well as the role of sex hormones in modulating this response, is of major health importance. This Project will follow up on our results indicating that male, but not female, rats develop T/HS-induced lung injury and endothelial cell activation/injury by testing the following two hypotheses. The first hypothesis is that T/HS-induced lung injury and increased endothelial cell permeability is secondary to gut injury and is mediated by factors exiting the gut via the mesenteric lymphatics but not the portal vein. The second hypothesis is that sex hormones modulate gut and hence distant organ injury in a model of T/HS. To test these hypotheses, we will first investigate the potential mechanisms of why the female gut is more resistant than the male gut to T/HS-induced gut injury and does not produce toxic lymph. Next, we will investigate the role of sex hormones as modulators of resistance and susceptibility to T/HS-induced gut and lung injury. We will investigate the hypothesis that estrogen protects against T/HS-induced gut injury by limiting iNOS induction. Lastly, we will investigate the mechanisms by which T/HS mesenteric lymph, alone or in combination with PMNs, increases vascular permeability and how this is influenced by gonadal hormonal manipulation.

外伤是 40 岁以下人群死亡的主要原因，MODS 是导致 40 岁以下人群死亡的主要原因 最初 72 小时受伤期间幸存的创伤患者死亡。事实上，MODS 是导致 今天在重症监护室死亡。尽管仍存在一些争议，但最近有证据表明，对 男性和女性之间的损伤和败血症可能有所不同，女性对不利因素的抵抗力更强 T/HS 的后果高于男性。因此，了解创伤出血的机制 休克（T/HS）导致 MODS，以及性激素在调节这种反应中的作用，是重要的 健康的重要性。该项目将跟进我们的结果，表明雄性大鼠而非雌性大鼠 通过测试以下两项来开发 T/HS 诱导的肺损伤和内皮细胞活化/损伤 假设。第一个假设是 T/HS 诱导的肺损伤和内皮细胞增加 通透性是肠道损伤的继发因素，由通过肠系膜排出肠道的因素介导 淋巴管，但不包括门静脉。第二个假设是性激素调节肠道，因此 T/HS 模型中的远端器官损伤。为了检验这些假设，我们将首先研究潜在的 为什么女性肠道比男性肠道对 T/HS 诱导的肠道损伤具有更强的抵抗力，并且确实如此 不会产生有毒的淋巴液。接下来我们将探讨性激素的作用 对 T/HS 诱导的肠道和肺损伤的抵抗力和易感性调节剂。我们将 研究雌激素通过限制 iNOS 来防止 T/HS 诱导的肠道损伤的假设 就职。最后，我们将研究 T/HS 肠系膜淋巴液单独或联合作用的机制。 与中性粒细胞结合，增加血管通透性以及这如何受到性腺激素的影响 操纵。