vx-770 and Pneumonia

Cystic fibrosis (CF) is caused by a defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) which instigates a myriad of respiratory complications including increased vulnerability to lung infections and lung inflammation. The extensive influx of pro-inflammatory cells and production of mediators into the CF lung leading to lung tissue damage and increased susceptibility to microbial infections, creates a highly inflammatory environment. The CF inflammation is particularly driven by neutrophil infiltration, through the IL-23/17 pathway, and function, through NE, NETosis, and NLRP3-inflammasome formation. Better understanding of these pathways may uncover untapped therapeutic targets, potentially reducing disease burden experienced by CF patients. This review outlines the dysregulated lung inflammatory response in CF, explores the current understanding of CFTR modulators on lung inflammation, and provides context for their potential use as therapeutics for CF. Finally, we discuss the determinants that need to be taken into consideration to understand the exaggerated inflammatory response in the CF lung.

Topics: Aminophenols; Aminopyridines; Anti-Inflammatory Agents; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Inflammation; Ion Transport; Lung; Macrophages; Pneumonia; Quinolones; Signal Transduction

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Mutation; Pneumonia; Quinolones

Thirty-one 4-oxoquinoline-3-carboxamides derivatives were synthesized and evaluated for their anti-fibrotic activities by the inhibition of TGF-β1-induced total collagen accumulation and anti-inflammatory activities by the inhibition of LPS-stimulated TNF-α production. Among them, three compounds (10a, 10l and 11g) exhibited potent inhibitory effects on both TGF-β1-induced total collagen accumulation and LPS-stimulated TNF-α production. Furthermore, oral administrations of 10l at a dose of 20 mg/kg/day for 4 weeks effectively alleviated lung inflammation and injury, and decreased lung collagen accumulation in bleomycin-induced pulmonary fibrosis model. Histopathological evaluation of lung tissue confirmed 10l as a potential, orally active agent for the treatment of pulmonary fibrosis.

Topics: 4-Quinolones; Animals; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Bleomycin; Cells, Cultured; Collagen; Lipopolysaccharides; Pneumonia; Pulmonary Fibrosis; Rats; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha