STUDY OF THE ROLE OF PLASMA MEMBRANE SPHINGOLIPIDS IN CYSTIC FIBROSIS AIRWAYS INFECTION

Cystic fibrosis (CF), the most common autosomal recessive disease among Caucasians, is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Among the wide spectrum of clinical and phenotypic manifestations occurring in CF, lung pathology is the main cause of morbidity and mortality. Progressive airway disease, chronic non-resolving inflammation, persistent bacterial infection are already observed in the majority of young children with CF. The prolonged airway inflammatory response induces permanent damage of CF airways leading to the loss of lung function in the majority of CF patients. In this respect, treatments with corticosteroids and ibuprofen have demonstrated potential benefits in CF patients, even though limited efficacy or the occurrence of side effects. For these reasons, the identification and the development of novel and more powerful anti-inflammatory drugs for CF airway disease remains a priority. Despite intensive research of the past few decades, the mechanisms involved in the onset of CF lung disease are not fully understood. Increasing lines of evidence highlighted the involvement of sphingolipids (SLs) in the development of CF lung pathology. SLs are cell membrane amphiphilic components that are located mainly in the external layer of the plasma membrane (PM) where they play important roles in the modulation of fundamental cell functions. Previous studies have demonstrated an abnormal SL metabolism in CF lung disease. In particular, increased levels of ceramide derived from sphingomyelin hydrolysis are related to the pro-inflammatory state as well as the inflammation response to bacterial infection occurring in CF lung disease. In addition, a recent study provides the evidence that ceramide derived from glycosphingolipid degradation (GSL) is involved in the inflammation response to bacterial infection of CF human epithelial bronchial cells; these data demonstrated that the pharmacological inhibition of GBA2, whose enzymatic activity produces ...