Regulation of pulmonary inflammation in cystic fibrosis by ceramide

囊性纤维化(CF)是西方国家最常见的常染色体隐性遗传病，由囊性纤维化跨膜传导调节因子(CFTR)分子突变引起，影响欧洲约4万名患者。这种疾病的特点是慢性肺部炎症，粘液纤毛清除减少，感染易感性增加。我们使用CFTR缺陷小鼠和人类CF标本进行的研究表明，神经酰胺在肺内积聚，并介导细胞死亡、感染易感性和炎症的增加。囊性纤维化肺(无菌性)炎症的分子机制尚未明确。在本研究中，我们旨在确定神经酰胺是否通过(1)CD95、caspase 1和炎症小体的激活，(2)紧密连接的功能障碍，(3)内皮细胞黏附蛋白的表达和功能的改变，以及(4)肺泡或巨噬细胞的调节失调，来介导CFTR基因缺陷小鼠肺部的慢性炎症。

Cystic fibrosis (CF), the most common autosomal recessive disorder in Western countries, is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) molecule and affects approximately 40 000 patients in Europe. The disease is characterized by chronic pulmonary inflammation, reduced mucociliary clearance, and increased susceptibility to infection. Our studies using Cftr-deficient mice and human CF specimens show that ceramide accumulates in the lungs and mediates increased cell death, susceptibility to infections, and inflammation. The molecular mechanisms of (aseptic) inflammation in cystic fibrosis lungs have not yet been defined. In the present study, we aim to determine whether ceramide mediates chronic inflammation in the lungs of Cftr-deficient mice through (i) activation of CD95, caspase 1 and the inflammasome, (ii) a dysfunction of tight junctions, (iii) an alteration of the expression and function of adhesion proteins in endothelial cells and (iv) a dysregulation of alvealor macrophages.