Regulation of pulmonary inflammation in cystic fibrosis by ceramide

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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.