Tumor necrosis factor, airway damage, and Cystic Fibrosis

http://www.ncbi.nlm.nih.gov/pubmed/21908587

Am J Physiol Lung Cell Mol Physiol. 2011 Sep 9. [Epub ahead of print]
Regulation of normal and cystic fibrosis airway epithelial repair processes by TNF{alpha} after injury.
Maille E, Trinh NT, Prive A, Bilodeau C, Bissonnette E, Grandvaux N, Brochiero E.
Source
1Centre de Recherche, CHUM-Hotel-Dieu.

Abstract
Chronic infection and inflammation have been associated with progressive airway epithelial damage in cystic fibrosis (CF) patients. 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 (TNFα), a major component of inflammation in CF, in a model of mechanical wounding, in 2 bronchial cell lines, non-CF NuLi and CF CuFi. We observed that TNFα enhanced the NuLi and CuFi repair rates. Chronic exposure (24-48 h) to TNFα 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 TNFα induced metalloproteinase-9 release, EGF shedding and subsequent EGFR trans-activation. Second, TNFα-induced stimulation of the NuLi and CuFi wound closure rates was prevented by GM6001 (metalloproteinase inhibitor), EGF-Ab (to titrate secreted EGF) and EGFR 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 TNFα enhances KvLQT1 and K(ATP) currents, while their inhibition abolishes TNFα-induced repair stimulation. These results indicate that TNFα's effect is mediated, at least in part, through EGFR trans-activation and K(+) channel stimulation. In contrast, cell proliferation during repair was slowed by TNFα, suggesting that TNFα could exert contrasting actions on repair mechanisms of CF airway epithelia. Finally, the stimulatory effect of TNFα on airway wound repair was confirmed on primary airway epithelial cells, from non-CF and CF patients.