Accumulation of ceramide in the trachea and intestine of cystic fibrosis mice causes inflammation and cell death

Cystic fibrosis is a hereditary metabolic disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and characterized by severe intestinal and pulmonary symptoms, in particular intestinal obstruction, pancreatic insufficiency, chronic pulmonary inflammation, and microbial lung infections. Recent studies have demonstrated an accumulation of ceramide in the lungs of cystic fibrosis patients and in several mouse models. These findings showed that pulmonary ceramide concentrations play an important role in pulmonary inflammation and infection. In this study we investigated whether ceramide concentrations are also altered in the trachea and the intestine of cystic fibrosis mice and whether an accumulation of ceramide in these organs has functional consequences that are typical of cystic fibrosis. Our findings demonstrate a marked accumulation of ceramide in tracheal and intestinal epithelial cells of cystic fibrosis mice. When acid sphingomyelinase activity is inhibited by treating cystic fibrosis mice with amitriptyline or by genetic heterozygosity of acid sphingomyelinase in cystic fibrosis mice, ceramide concentrations in the trachea and the intestine are normalized. Moreover, increased rates of cell death and increased cytokine concentrations in the trachea, the intestine, or both were normalized by the inhibition of acid sphingomyelinase activity and the concomitant normalization of ceramide concentrations. These findings suggest that ceramide plays a crucial role in inflammation and increased rates of cell death in several organs of cystic fibrosis mice.

Research highlights
► Cystic fibrosis mice accumulate ceramide in epithelial cells of the trachea and the gut.
► Ceramide causes death of epithelial cells in the trachea and the gut.
► Ceramide triggers chronic inflammation in the trachea.
► These alterations are normalized by genetic or pharmacological inhibition of ceramide release.
► The data suggest a novel mechanism for the treatment of cystic fibrosis.