OSMOTIC REGULATION OF MACROPHAGES IN CYSTIC FIBROSIS

囊性纤维化中巨噬细胞的渗透压调节

• 批准号: 6608584
• 负责人: David W. Riches
• 金额: $ 30.76万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6608584
• 关键词: alveolar macrophages; apoptosis; athymic mouse; cell migration; cell transplantation; cellular pathology; chloride channels; cystic fibrosis; interleukin 8; laboratory rat; mitogen activated protein kinase; neutrophil; osmotic pressure; respiratory epithelium; xenotransplantation

DESCRIPTION (adapted from the application): It has been proposed that in cystic fibrosis, the defective cystic fibrosis transmembrane regulator (CFTR) gene is responsible for hypersecretion and/or malabsorption of NaCl in airway epithelia leading to marked elevations in NaCl in airway surface liquid (ASL). Previous studies from this investigative team have shown that the pro-inflammatory chemokine, IL-8, is produced by macrophages in CF at an early age thereby contributing to neutrophil accumulation in the airways. In this proposal, the investigator addresses the mechanism by which osmolality may regulate macrophage function in CF. In preliminary studies, he has shown that changes in osmolality greatly potentiate pro-inflammatory chemokine production by macrophages, as well as by potentiating monocyte apoptosis. The goals of this proposal are to investigate the mechanisms by which hyperosmolality changes monocyte and macrophage function. The investigator hypotheses that increased chemokine production will result in increased neutrophil presence in the airways, while increased monocyte apoptosis will remove an important vehicle of neutrophil clearance. These goals will be addressed by three specific aims. Specific Aim 1 will address the mechanism of potentiation of IL-8 production by modest hyperosmolality and test the hypothesis that the mechanism involves JNK activation, AP-1 transactivation, and a hyperosmolality responsive element in the IL-8 promoter. Specific Aim 2 will investigate the mechanism of increased apoptosis in the presence of modest hyperosmolality. Based on preliminary findings, the investigator hypothesizes that the mechanisms will involve concurrent activation of p38 MAP kinase and inhibition of pro-survival signals conferred by either p42 ERK and/or Akt. Specific Aim 3 will investigate the pro-inflammatory chemokine production and apoptosis in a relevant in vivo model of CF airways involving bronchial epithelial cell xenografts in nude mice using epithelial cells from normal and CF-lungs. These studies are expected to provide novel, important insights into the role of the defective CFTR in promoting pulmonary inflammation in cystic fibrosis.

描述（改编自应用程序）：有人提出，在囊性 在纤维化中，有缺陷的囊性纤维化跨膜调节因子（CFTR）基因是 导致气道上皮细胞中NaCl分泌过多和/或吸收不良 导致气道表面液体（ASL）中的NaCl显著升高。先前 这个研究小组的研究表明， 趋化因子IL-8由CF中的巨噬细胞在早期产生， 导致嗜中性粒细胞在气道中积聚。在本提案中， 研究者阐述了渗透压摩尔浓度可能调节的机制 CF中的巨噬细胞功能。在初步研究中，他已经表明， 渗透压摩尔浓度极大地增强了促炎趋化因子的产生， 巨噬细胞，以及通过增强单核细胞凋亡。这个的目标 建议是调查高渗透压变化的机制 单核细胞和巨噬细胞功能。研究人员假设， 趋化因子的产生将导致增加的中性粒细胞存在于 而单核细胞凋亡的增加将消除一个重要的载体， 中性粒细胞清除率这些目标将通过三个具体目标来实现。 具体目标1将通过以下方式阐明增强IL-8产生的机制： 适度的高渗透压，并检验其机制涉及JNK的假设 激活、AP-1反式激活和高渗反应元件， IL-8启动子。具体目标2将研究增加的机制 在适度高渗存在下的细胞凋亡。根据初步 调查结果，研究人员假设，机制将涉及 同时激活p38 MAP激酶和抑制促存活信号 由p42 ERK和/或Akt赋予。具体目标3将调查 相关体内模型中促炎趋化因子的产生和细胞凋亡 CF气道涉及支气管上皮细胞异种移植物在裸鼠中使用 来自正常和CF肺的上皮细胞。这些研究预计将 提供了新的，重要的见解，有缺陷的CFTR的作用， 促进囊性纤维化的肺部炎症。