LIPIDOMICS UNVEILS THE ROLE OF BIOACTIVE LIPIDS IN CELLULAR MODELS OF CYSTIC FIBROSIS

Cystic fibrosis is a genetic disease affecting mainly the lungs, causing chronic inflammation and recurrent infections. The lipid accrual directly contributes to the persistent damage in the cystic fibrosis airways; thus, the deregulated lipid metabolism can be targeted with pharmacological treatment. Here, we aim at demonstrating, in an in vitro model of cystic fibrosis, the role of inflammatory and bioactive lipids in the disease pathophysiology and its modulation by myriocin, which inhibits sphingolipids synthesis. The blended use of both targeted and untargeted mass spectrometry techniques unveiled an atypical lipid composition in broncho-epithelial cystic fibrosis cells and the derived extracellular vesicles. The airways cells in cystic fibrosis accumulate lipids, exacerbating inflammation that can be partly reversed by myriocin therapy, which acts directly on sphingolipid synthesis and indirectly on the accrual of other lipid classes. The CFTR dysfunction leads to an increased metabolism of sphingolipids, which in turn is connected to the release of ceramide-enriched extracellular vesicles that export a pro-inflammatory signal to the recipient cells. The accumulation of lipids may be the result of dysfunctional lipid traffic in the cell and may be responsible for blocking the ER-Golgi network, overproduction of reactive oxygen species and uncontrolled inflammatory stimuli. We proposed new insights on the role of lipid metabolism in the development of cystic fibrosis pathogenesis by using a validated mass spectrometry lipidomics approach. To conclude, we hypothesize that the metabolism of sphingolipids may be an effective pharmacological target to help the reduction of the intrinsic inflammatory state in the airways.