NEUTROPHILS AND G-CSF IN HEMORRHAGIC SHOCK

失血性休克中的中性粒细胞和 G-CSF

• 批准号: 6271867
• 负责人: DAVID TWEARDY
• 金额: $ 10.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6271867
• 关键词: CD antigens; antibody receptor; colony stimulating factor; cytokine receptors; hemorrhagic shock; human tissue; interleukin 8; laboratory mouse; laboratory rat; leukocyte activation /transformation; lipopolysaccharides; molecular cloning; molecular pathology; multiple organ failure; neutrophil; nitric oxide synthase; protein biosynthesis; protein sequence; respiratory transplantation; tissue /cell culture; transcription factor

In animals or humans suffering the consequences of hemorrhagic shock (HS), polymorphonuclear neutrophilic granulocytes (PMN) are the major cellular element that mediates the inflammatory process. We propose that PMN activation is an early event in HS initiated by the consequences of ischemia and resuscitation which includes the production and action of granulocyte colony-stimulating factor (G-CSF). We have demonstrated elevated G-CSF mRNA levels in critical organs including the lung, liver, and bowel in our rat model of HS. Levels of G-CSF mRNA increased with increasing severity of HS. We have identified bronchial epithelial cells as the major cellular source of G-CSF production in the lung in HS. In addition to our findings in rats, we have observed a 55-fold increase in G-CSF mRNA production in the livers of patients with HS. To establish that G-CSF production in the organs of animals and patients with HS is deleterious to the host, we demonstrated that instillation of G-CSF alone into the lungs of rats results in PMN recruitment and lung damage. In related work, we have shown that G-CSF specifically activates a distinct member of the signal transduction and activator of transcription (STAT) family, Stat3(, in PMN. PMN of rats subjected to HS revealed greater Stat3( activity than sham animals. In addition, PMN from patients suffering from HS showed clear evidence of G-CSF-induced Stat3( activation. Taken together, our findings to date strongly support the hypothesis that G-CSF is produced in critical organs in HS where it binds to PMN resulting in organ inflammation. The overall goal of this proposal is determine how G-CSF production occurs in HS and how its production leads to PMN recruitment and activation in HS and its morbid sequellae. Towards this end, the two Specific Aims of this project are: AIM I: To determine the consequences of G-CSF production on PMN recruitment, Stat3( activation, and organ injury in HS and to examine the effect of blocking the G-CSF signaling pathway in PMN on morbidity and mortality of HS. AIM II: To determine the factors contributing to G-CSF production at critical sites of PMN recruitment and organ injury.

在遭受失血性休克(HS)后果的动物或人类中， 中性粒细胞(PMN)是主要的细胞。 调节炎症过程的元素。我们建议PMN 激活是HS中由以下后果引发的早期事件 缺血和复苏，包括产生和作用于 粒细胞集落刺激因子(G-CSF)。我们已经证明了 肺、肝等重要器官G-CSF mRNA水平升高， 以及我们的HS大鼠模型中的肠道。G-CSF信使核糖核酸水平随 HS的严重性不断增加。我们已经鉴定出了支气管上皮细胞 是HS患者肺组织产生G-CSF的主要细胞来源。在……里面 除了我们在老鼠身上的发现外，我们还观察到 HS患者肝脏中G-CSF mRNA的表达。要确立这一点 动物和HS患者器官中G-CSF的产生 对宿主有害，我们证明了单独滴注G-CSF 进入大鼠肺内会导致PMN募集和肺损伤。在……里面 相关工作，我们已经证明了G-CSF特异性地激活了一个独特的 信号转导和转录激活因子(STAT)成员 家庭，状态3(，在PMN中。高压性惊厥大鼠中性粒细胞数量增加 STAT3(比假动物更活跃。此外，患者的中性粒细胞 患HS的患者有明确证据表明G-CSF诱导的STAT3( 激活。综上所述，我们到目前为止的发现有力地支持了 假设G-CSF在HS的关键器官中产生并与之结合 到中性粒细胞，导致器官炎症。这项提案的总体目标是 是确定在HS中G-CSF是如何产生的以及它是如何产生的 导致中性粒细胞在HS及其病态后遗症中的募集和激活。 为此，该项目的两个具体目标是： 目的I：确定粒细胞集落刺激因子产生对中性粒细胞的影响 在HS中招募、STAT3(激活)和器官损伤，并检查 阻断中性粒细胞G-CSF信号通路对发病及预后的影响 HS死亡率。 目的II：确定影响G-CSF产生的因素 中性粒细胞招募和器官的关键部位 受伤。