Clearance of Apoptotic Cells in Cystic Fibrosis

囊性纤维化中凋亡细胞的清除

• 批准号: 6562269
• 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/6562269
• 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）： 囊性纤维化 (CF) 是一种常染色体隐性遗传疾病，由囊性纤维化跨膜电导调节因子 (CFTR) 突变引起，与慢性、衰弱性气道炎症相关。在囊性纤维化中，气道炎症几乎在出生后立即开始，并无情地持续下去，直到大多数患者因肺衰竭而死亡。研究观察到，在没有可检测到的感染的情况下，CF 新生儿气道中炎症细胞和介质的积累，表明 CFTR 缺陷可能有能力扰乱正常的调节机制，并引发气道炎症。炎症的解决通常涉及有序清除凋亡的炎症细胞，从而抑制其造成损害的能力。该过程通过以下方式促进炎症消退：1) 防止促炎细胞内容物溢出；2) 通过与磷脂酰丝氨酸受体相互作用，诱导吞噬细胞产生抗炎介质，例如 TGFI3 和 PGE2。我们观察到，凋亡的炎症细胞在患有 CF 的年轻人的气道中积聚，并表明 PS 受体的蛋白酶裂解参与其中。我们现在提供的证据表明，CFTR 缺陷会损害气道上皮对凋亡细胞的摄取，并阻止凋亡细胞抑制炎症介质的释放。 CFTR 在上皮细胞清除凋亡细胞中的作用可能与 CFTR 是 ATP 结合盒 (ABC) 蛋白超家族的成员有关，该超家族包括已知与凋亡细胞清除有关的成员（例如 ced7 和 ABC-1）。这些发现和上皮细胞在凋亡细胞清除中的已知作用表明，上皮细胞的吞噬作用失败可能导致凋亡细胞的积累和 CF 气道中的持续炎症。因此，我们建议1）测试CFTR对凋亡细胞独特摄取机制的影响，2）测试凋亡细胞可能增强CFTR缺陷的上皮细胞炎症反应的各种机制，以及3）确定功能失调的CFTR对体内凋亡细胞清除和炎症的影响。这些研究将有助于阐明 CFTR 在以前未知的功能、凋亡细胞的吞噬作用和炎症调节中的作用，并且在未来可能有助于指导减轻这一过程和减少慢性气道炎症的长期影响的治疗。