title: Regulation of normal and cystic fibrosis airway epithelial repair processes by TNF-α after injury.
abstract: Chronic infection and inflammation have been associated with progressive airway epithelial damage in patients with cystic fibrosis (CF). However, the effect of inflammatory products on the repair capacity of respiratory epithelia is unclear. Our objective was to study the regulation of repair mechanisms by tumor necrosis factor-α (TNF-α), a major component of inflammation in CF, in a model of mechanical wounding, in two bronchial cell lines, non-CF NuLi and CF CuFi. We observed that TNF-α enhanced the NuLi and CuFi repair rates. Chronic exposure (24-48 h) to TNF-α augmented this stimulation as well as the migration rate during repair. The cellular mechanisms involved in this stimulation were then evaluated. First, we discerned that TNF-α induced metalloproteinase-9 release, epidermal growth factor (EGF) shedding, and subsequent EGF receptor transactivation. Second, TNF-α-induced stimulation of the NuLi and CuFi wound-closure rates was prevented by GM6001 (metalloproteinase inhibitor), EGF antibody (to titrate secreted EGF), and EGF receptor tyrosine kinase inhibitors. Furthermore, we recently reported a relationship between the EGF response and K(+) channel function, both controlling bronchial repair. We now show that TNF-α enhances KvLQT1 and K(ATP) currents, while their inhibition abolishes TNF-α-induced repair stimulation. These results indicate that the effect of TNF-α is mediated, at least in part, through EGF receptor transactivation and K(+) channel stimulation. In contrast, cell proliferation during repair was slowed by TNF-α, suggesting that TNF-α could exert contrasting actions on repair mechanisms of CF airway epithelia. Finally, the stimulatory effect of TNF-α on airway wound repair was confirmed on primary airway epithelial cells, from non-CF and CF patients.
authors: Centre de recherche, Centre hospitalier de l’Université de Montréal, Hôtel-Dieu, Montréal, Québec, Canada.
authors: Emilie
authors: E
authors: Maillé
authors: Nguyen Thu Ngan
authors: NT
authors: Trinh
authors: Anik
authors: A
authors: Privé
authors: Claudia
authors: C
authors: Bilodeau
authors: Elyse
authors: E
authors: Bissonnette
authors: Nathalie
authors: N
authors: Grandvaux
authors: Emmanuelle
authors: E
authors: Brochiero
mesh_terms: D055745:Bronchioles / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000378:metabolism / Q000473:pathology*; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D066246:ErbB Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D061251:Primary Cell Culture; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D000644:Quaternary Ammonium Compounds; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; C022799:clofilium; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9