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

Maillé E, Trinh NT, Privé A, Bilodeau C, Bissonnette E, Grandvaux N, Brochiero E.
Source: Am J Physiol Lung Cell Mol Physiol
Publication Date: (2011)
Issue: 301(6): L945-55
Research Area:
Basic Research
Cells used in publication:
Epithelial, airway, human
Species: human
Tissue Origin: lung
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-a (TNF-a), 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-a enhanced the NuLi and CuFi repair rates. Chronic exposure (24-48 h) to TNF-a 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-a induced metalloproteinase-9 release, epidermal growth factor (EGF) shedding, and subsequent EGF receptor transactivation. Second, TNF-a-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-a enhances KvLQT1 and K(ATP) currents, while their inhibition abolishes TNF-a-induced repair stimulation. These results indicate that the effect of TNF-a is mediated, at least in part, through EGF receptor transactivation and K(+) channel stimulation. In contrast, cell proliferation during repair was slowed by TNF-a, suggesting that TNF-a could exert contrasting actions on repair mechanisms of CF airway epithelia. Finally, the stimulatory effect of TNF-a on airway wound repair was confirmed on primary airway epithelial cells, from non-CF and CF patients.