Vx-809/Vx-770 treatment reduces inflammatory response to Pseudomonas aeruginosa in primary differentiated cystic fibrosis bronchial epithelial cells

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Abstract
Cystic fibrosis patients exhibit chronic P. aeruginosa respiratory infections and sustained pro-inflammatory state favoring lung tissue damage and remodeling, ultimately leading to respiratory failure. Loss of CFTR function is associated with MAPK hyper-activation and increased cytokines expression, such as the interleukin 8 (CXCL8). Recently, new therapeutic strategies directly targeting the basic CFTR defect have been developed and ORKAMBI (Vx-809/Vx-770 combination) is the only FDA-approved treatment for CF patients homozygous for the F508del mutation. Here we aimed to determine the effect of the Vx-809/Vx-770 combination on the induction of the inflammatory response by fully-differentiated primary bronchial epithelial cell cultures from CF patients carrying F508del mutations, following exposure to P. aeruginosa exoproducts. Our data unveiled that CFTR functional rescue with Vx-809/Vx-770 drastically reduces CXCL8 (as well as CXCL1 and CXCL2) transcripts and p38 MAPK phosphorylation in response to P. aeruginosa exposure through a CFTR-dependent mechanism. These results suggest that ORKAMBI has anti-inflammatory properties that could decrease lung inflammation and contribute to the observed beneficial impact of this treatment in CF patients.
Funding Information
  • Cystic Fibrosis Canada (Fibrose kystique Canada) (2368, 2595)
  • CRCHUM
  • Université de Montréal
  • Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de recherche en santé du Canada) (MOP#123496, PJT#148593)
  • Association Vaincre la Mucoviscidose (RF20160501674, RF20160501674)
  • Fonds de Recherche du Québec - Santé (Fonds de la recherche en sante du Quebec)
  • Respiratory Health Network of Les Fonds de Recherche du Québec-Santé (FRQ-S)

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