Fig. (2).

Effects of ceramide in cystic fibrosis. Alkalinization of intracellular vesicles, most likely secretory lysosomes, in CF-cells results in an imbalance of the activities of the acid sphingomyelinase and the acid ceramidase. The increase of the intravesicular pH to approximately pH 6 reduces the activity of the acid sphingomyelinase, which releases ceramide from sphingomyelin, by only 30-40%, while the activity of the acid ceramidase, which consumes ceramide, is reduced by more than 90%. Ceramide may then accumulate in CF cells as the net effect of the pH-mediated imbalance between the acid sphingomyelinase and the acid ceramidase. Ceramide induces cell death with subsequent deposition of DNA in the airways, chronic inflammation as indicated by accumulation of neutrophils, macrophages and proinflammatory cytokines such as Interleukin 1 and 8 in lung tissues and high susceptibility to P. aeruginosa infections. Genetic or pharmacological inhibition of the acid sphingomyelinase normalizes pulmonary ceramide, cell death, inflammation and infection susceptibility.