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: 2621743
• 负责人: Jonathan H Widdicombe
• 金额: $ 90.46万
• 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/2621743
• 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将测试两个基本假设，以解释CF相关 气道表面液体（ASL）的改变导致 假单胞菌浆液性细胞功能障碍假说认为， 在大气道的粘膜下腺体中的细胞和 小气道显示CF中液体和抗生素的分泌减少。的 导致浆液细胞抗生素水平降低和粘蛋白增加 ASL中的浓度有利于病原体定殖。高盐 一种假说提出人气道上皮吸收Na和Cl， 大部分Cl吸收通过跨细胞途径发生， 并且由于CFTR故障而导致的该路线的阻塞比 CF中ASL的正常NaCl含量。一个不太可能的可能性是， CF ASL中的NaCl水平升高是由比正常腺体更咸引起的 由于导管盐吸收失败而导致的分泌物。高盐 ASL的含量可能通过抑制细菌的生长而促进假单胞菌的定植。 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深度的调节是如何进行的。 在CF中改变。ASL和腺体的盐和粘蛋白含量随深度变化， ASL在活组织中的组成和粘度， 荧光显微镜项目3（葡萄酒）将研究分泌 有助于ASL的机制，并专门测试浆液细胞 故障假说项目4（米勒）将确定路线， Na和Cl通过气道表面吸收的机制 上皮鼻PD测量将用于体外验证 调查结果。细胞培养核心（Finkbeiner）将提供完整的人类 气道和人类腺体和表面上皮细胞的培养物。