Clearance of Apoptotic Cells in Cystic Fibrosis

囊性纤维化中凋亡细胞的清除

• 批准号: 7010714
• 负责人: RICHARD W VANDIVIER
• 金额: $ 13.07万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-17 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7010714
• 关键词: apoptosis; biological signal transduction; calreticulin; chloride channels; clinical research; cystic fibrosis; epidermal growth factor; flow cytometry; genetically modified animals; growth factor receptors; human tissue; inflammation; laboratory mouse; laboratory rat; respiratory epithelium; scanning electron microscopy; terminal nick end labeling; tissue /cell culture; transforming growth factors; western blottings

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is an autosomal recessive disorder caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) that is associated with chronic, debilitating airway inflammation. In CF, airway inflammation begins almost immediately following birth and continues inexorably until death ensues from pulmonary failure in the majority of patients. Studies have observed the accumulation of inflammatory cells and mediators in the airways of CF neonates in the absence of detectable infection, suggesting that CFTR-deficiency may have the capacity to disturb normal regulatory mechanisms, and initiate airway inflammation. Resolution of inflammation normally involves the orderly removal of apoptotic inflammatory cells, thereby suppressing their ability to do damage. This process promotes the resolution of inflammation by, 1) preventing spillage of proinflammatory cell contents, and by 2) inducing the phagocyte to produce anti-inflammatory mediators such as TGFI3 and PGE2, through interaction with the phosphatidylserine receptor. We have observed that apoptotic inflammatory cells accumulate in the airways of young adults with CF, and have shown that protease cleavage of the PS receptor is involved. We now provide evidence that CFTR-deficiency impairs apoptotic cell ingestion by airway epithelium, and prevents apoptotic cell suppression of inflammatory mediator release. A role for CFTR in epithelial cell clearance of apoptotic cells may be related to the fact that CFTR is a member of the ATP-binding cassette (ABC) protein superfamily, which includes members known to be involved with apoptotic cell removal (e.g. ced7 and ABC-1). These findings and the known role for epithelial cells in apoptotic cell clearance suggest that failed phagocytosis by epithelial cells may contribute to the accumulation of apoptotic cells and persistent inflammation in CF airways. Therefore, we propose to 1) test the effect of CFTR on ingestion mechanisms unique to uptake of apoptotic cells, to 2) test various mechanisms whereby apoptotic cells may enhance the inflammatory response in CFTR-deficient epithelial cells, and to 3) determine the effect of dysfunctional CFTR on apoptotic cell clearance and inflammation in vivo. These studies will help to elucidate the role of CFTR in a previously unknown function, phagocytosis of apoptotic cells and regulation of inflammation, and in the future may help direct therapies toward mitigating this process and diminishing the long-term effects of chronic airway inflammation.

描述（由申请人提供）：