ALTERATIONS IN AIRWAY SURFACE LIQUID IN CYSTIC FIBROSIS

囊性纤维化时气道表面液体的变化

• 批准号: 6056520
• 负责人: Jonathan H Widdicombe
• 金额: $ 89.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6056520
• 关键词: cystic fibrosis; respiratory epithelium

The proposed SCOR will test two basic hypothesis to explain the CF-related modifications in airway surface liquid (ASL) that lead to colonization by Pseudomonas. The serous cell malfunction hypothesis proposes that serous cells in the submucosal glands of large airways and on the surface of small airways show reduced secretion of fluid and antibiotics in CF. The resulting decreased levels of serous cell antibiotics and increased mucin concentrations in ASL favor pathogen colonization. The high salt hypothesis proposes that human airway epithelium absorbs Na and Cl, that a substantial fraction of Cl absorption occurs by an transcellular route, and that block of this route by malfunction of CFTR promotes higher than normal NaCl content of ASL in CF. A less likely possibility is that elevated NaCl levels in CF ASL are caused by saltier than normal gland secretions resulting from failure of ductal salt absorption. High salt content of ASL may encourage Pseudomonas colonization by inhibiting the action of natural antibiotics. Project 1 (Widdicombe/Bastacky) will use low-temperature scanning electron microscopy and X-ray microanalysis of rapidly frozen tissues to determine how the regulation of ASL depth is altered in CF. Salt and mucin content of ASL and gland changes in depth, composition and viscosity of ASL in living tissues using novel fluorescence microscopy. Project 3 (Wine) will study the secretory mechanisms contributing to the ASL, and test specifically the serous cell malfunction hypothesis. Project 4 (Miller) will determine the routes and mechanisms by which Na and Cl are absorbed across airway surface epithelium. Nasal PD measurements will be used to verify in vitro findings. A Cell Culture Core (Finkbeiner) will provide intact human airways and cultures of human gland and surface epithelial cells.

拟议的SCOR将检验两个基本假设，以解释与CF相关的 呼吸道表面液体(ASL)中导致定植的修饰 假单胞菌。浆液性细胞功能障碍假说提出浆液性细胞功能障碍 大气道粘膜下腺和粘膜表面的细胞 小气道表现为CF中液体和抗生素的分泌减少。这个 导致血清细胞抗生素水平下降和粘蛋白增加 ASL中的浓度有利于病原菌定植。高盐度 假说认为人的呼吸道上皮吸收钠和氯， 很大一部分氯吸收是通过跨细胞途径进行的， 且CFTR故障对该路径的阻塞率高于 CF中ASL的正常氯化钠含量。一种不太可能的可能性是 CFASL中氯化钠水平升高是由腺体比正常盐度高引起的 由于导管对盐的吸收失败而导致的分泌物。高盐 ASL的含量可能通过抑制假单胞菌的生长而促进其定植 天然抗生素的作用。项目1(Widdicombe/Bastacky)将使用 低温扫描电子显微镜和X射线微区分析 快速冷冻组织以确定ASL深度的调节如何 在配置文件中更改。ASL和腺体的盐分和粘蛋白含量随深度变化， 新型ASL在活体组织中的组成和粘度 荧光显微镜。项目3(葡萄酒)将研究 导致ASL的机制，并特别测试浆液细胞 故障假说。项目4(米勒)将确定路线和 钠和氯在呼吸道表面的吸收机制 上皮组织。鼻腔PD测量将用于体外验证 调查结果。一个细胞培养核心(Finkbeiner)将提供完整的人类 人体腺体和表面上皮细胞的呼吸道和培养。