MONDAY, March 31 (HealthDay News) -- An age-dependent increase in ceramide levels in the lungs of mice with cystic fibrosis causes many of the symptoms of the disease, which can be reversed by an inhibitor that normalizes ceramide levels, according to research published online March 30 in Nature Medicine.
Volker Teichgraber, from the University of Duisburg-Essen in Germany, and colleagues examined the role of sphingolipids in the pathogenesis of cystic fibrosis using mice lacking the cystic fibrosis transmembrane conductance regulator gene in the respiratory tract.
The researchers found an age-dependent increase in ceramide in the lungs of these mice compared with wild-type mice. Further experiments showed that this increase was due to alkalinization of intracellular vesicles, which shifted the balance between acid sphingomyelinase (Asm) cleavage of sphingomyelin to ceramide and acid ceramidase consumption of ceramide. The accumulation of ceramide led to pulmonary inflammation, death of respiratory epithelial cells, DNA deposition in bronchi and susceptibility to infection, which could be reversed by the Asm inhibitor amitriptyline.
"In summary, our data identify ceramide as one of the key regulators of inflammation and subsequent infection in cystic fibrosis airways," Teichgraber and colleagues conclude. "These findings suggest that normalization of ceramide levels by amitriptyline may represent a new and important strategy to prevent bacterial infections in people with cystic fibrosis."
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