Regulation of normal and cystic fibrosis airway epithelial repair processes by TNF-α after injury

Maille E, Trinh NT, Prive A, Bilodeau C, Bissonnette E, Grandvaux N, Brochiero E. Regulation of normal and cystic fibrosis airway epithelial repair processes by TNF-alpha after injury. Am J Physiol Lung Cell Mol Physiol 301: L945-L955, 2011. First published September 9, 2011; doi: 10.1152/ajplung.00149.2011.-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-alpha (TNF-alpha), 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-alpha enhanced the NuLi and CuFi repair rates. Chronic exposure (24-48 h) to TNF-alpha 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-alpha induced metalloproteinase-9 release, epidermal growth factor (EGF) shedding, and subsequent EGF receptor transactivation. Second, TNF-alpha -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-alpha enhances KvLQT1 and K-ATP currents, while their inhibition abolishes TNF-alpha-induced repair stimulation. These results indicate that the effect of TNF-alpha is mediated, at least in part, through EGF receptor transactivation and K+ channel stimulation. In contrast, cell proliferation during repair was slowed by TNF-alpha, suggesting that TNF-alpha could exert contrasting actions on repair mechanisms of CF airway epithelia. Finally, the stimulatory effect of TNF-alpha on airway wound repair was confirmed on primary airway epithelial cells, from non-CF and CF patients.