Expression of Intestinal and Lung Alkaline Sphingomyelinase and Neutral Ceramidase in Cystic Fibrosis F508del Transgenic Mice

Objectives: The intestinal brush border enzymes alkaline sphingomyelinase (alk-SMase) and neutral ceramidase (CDase) digest milk sphingomyelin in suckling neonates. In addition alk-Smase, CDase, and acid sphingomyelinase (acid-SMase) have been implicated in sphingolipid signaling, which exhibits abnormalities in cystic fibrosis (CF). In this study, we tested the hypothesis that the expression of these enzymes is different in CF. Materials and Methods: We used mice with F508del (Cftr(tmlEur)) mutation. a CF mouse model with well-characterized intestinal pathology, Enzyme activities were measured using radiolabeled sphingolipid substrates incubated with tissue homogenates from different organs and intersinal contents of wild-type mice. homozygous, and heterozygous F508del mice. Results: No difference was found in levels of CDase and alk-SMase in the small intestinal mucosa or in their longitudinal distribution. Acid-SMase activity was significantly lower in the mucosa of the distal half of the small intestine of F508del compared with wild-type mice. Despite a lower body weight of F508del mice, length and weight of the small intestine and weight per centimeter of colon were larger than in wild-type Neutral CDase and alk-SMase activities in lungs were lower than in the gut, whereas acid-SMase activity was comparable in both organs. CDase activity in the spleen was significantly higher in F508del than in wild-type mice. Conclusions: Alk-SMase and neutral CDase are normally expressed in F508del CF mice. whereas activity of acid-SMase in the distal small intestine is decreased. We found no differences in activity of these enzymes in lungs in this mouse model. JPGN 47:547-554, 2008.