Clearance of Apoptotic Cells in Cystic Fibrosis

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病，由囊性纤维化跨膜传导调节因子(CFTR)突变引起，与慢性、衰弱的呼吸道炎症有关。在慢性阻塞性肺疾病中，呼吸道炎症几乎在出生后立即开始，并持续到大多数患者因肺功能衰竭而死亡。已有研究观察到，在未发现感染的情况下，炎症细胞和介质在CF新生儿的呼吸道中积聚，提示CFTR缺乏可能具有扰乱正常调节机制的能力，并启动呼吸道炎症。炎症的消退通常包括有序地清除凋亡的炎症细胞，从而抑制它们造成损害的能力。这一过程通过以下方式促进炎症的消退：1)防止前炎症细胞内容物溢出，2)通过与磷脂酰丝氨酸受体的相互作用，诱导吞噬细胞产生抗炎介质，如TGFI3和PGE2。我们观察到年轻成人CF患者的呼吸道内有大量的炎性细胞凋亡，并表明PS受体的蛋白水解酶参与了这一过程。我们现在提供的证据表明，CFTR缺乏损害了呼吸道上皮细胞对凋亡细胞的摄取，并阻止了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，该超家族包括已知的与凋亡细胞清除有关的成员(如ced7和abc-1)。这些发现和上皮细胞在细胞凋亡清除中的已知作用表明，上皮细胞吞噬失败可能是导致CF呼吸道内细胞凋亡和持续炎症的原因之一。因此，我们建议1)测试CFTR对摄取凋亡细胞特有的摄取机制的影响，2)测试凋亡细胞可能增强CFTR缺陷上皮细胞炎症反应的各种机制，以及3)在体内确定功能障碍的CFTR对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、凋亡细胞吞噬和炎症调节中的作用，并在未来可能有助于指导减轻这一过程和减少慢性气道炎的长期影响的治疗。

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.