Acid ceramidase rescues cystic fibrosis mice from pulmonary infections.

Previous studies have shown that sphingosine kills a variety of pathogenic bacteria, including Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus Sphingosine concentrations are decreased in airway epithelial cells of cystic fibrosis (CF) mice and this defect has been linked to the infection susceptibility of these mice. Here, we tested whether genetic overexpression of the acid ceramidase rescues cystic fibrosis mice from pulmonary infections with P. aeruginosa We demonstrate that transgenic overexpression of the acid ceramidase in CF mice corresponds to an overexpression of the acid ceramidase in bronchial and tracheal epithelial cells and normalizes ceramide and sphingosine levels in bronchial and tracheal epithelial cells. In addition, expression of β1-integrin, which is ectopically expressed on the luminal surface of airway epithelial cells in cystic fibrosis mice - an alteration that is very important for mediating pulmonary P. aeruginosa infections of cystic fibrosis, is normalized in cystic fibrosis airways upon overexpression of acid ceramidase. Most importantly, overexpression of acid ceramidase protects cystic fibrosis mice from pulmonary P. aeruginosa infections. Infection of CF mice or CF mice that were inhaled with sphingosine with P. aeruginosa or a P. aeruginosa mutant that is resistant to sphingosine indicate that sphingosine and not a metabolite kills P. aeruginosa upon pulmonary infection. These studies further support the use of acid ceramidase and its metabolite sphingosine as a potential treatment of cystic fibrosis.