Grant: Project Grant

The cystic fibrosis (CF) protein (CFTR) ensures the normal water and ion composition of the liquid that lines the airway. Mutations in CF impair the CFTR function and the composition of the airway surface liquid layer. This leads to lung inflammation, which is further exacerbated by infection, the primary cause of premature death in CF. Pseudomonas aeruginosa bacteria cause the most common infection of the CF lung, with ~80% of CF patients becoming chronically infected, which lead to faster loss of lung function and decreased survival, partly due to the inherently hyper-responsive state of the CF lung prior to infection and to the P. aeruginosa virulence factors that attenuate both the mutant CFTR functional expression and the efficacy of CFTR folding correctors. P. aeruginosa also evokes an excessive innate immune response, characterized by cytokines, lipid mediators and elastase release, neutrophil influx, which further compromise the mutant CFTR function. Here we propose to elucidate the underlying molecular basis of the sterile inflammation, associated with the human CF bronchial epithelia (CF-HBE) or nasal epithelia (CF-HNE) cultures in the absence or presence of white blood cells. Similar studies will be performed in the presence of bacteria secretion, enabling us to study the inflammatory mediator activation time course and the mutant CFTR function in presence and absence of CFTR corrector drugs, as well as upon various interventions that suppress the innate immune response. CFTR functional rescue will include a recently identified surface receptor that can modulate the inflammatory signalling in the absence of CFTR. To capture the variability of cellular responses to CFTR modulators and innate immune signaling among CF patients, HNE and HBE collected from 20 patients homozygous for the F508del mutation will be used in the proposed model. The results may pinpoint novel approaches to suppress the excessive sterile inflammation of the CF lung.