Régulation des processus de réparation de l’épithélium bronchique sain et Fibrose Kystique par le TNF-alpha
Cystic fibrosis (CF) pathology, caused by mutations of cftr gene, leads to ion and fluid transport dysfunction that results in mucus thickening and accumulation in the airways. This mucus accumulation promotes bacterial infection and airway inflammation associated with progressive airway epithelial damage in CF patients, unfortunately leading to respiratory failure. However, the effect of inflammatory products on the repair capacity of respiratory epithelia is unclear. Thus, the objective of my project was to study the regulation of normal and CF bronchial epithelial repair mechanisms by tumor necrosis factor-alpha (TNF)-alpha, a major component of inflammation initiation and propagation in CF. With a wound healing model, we observed that TNF-alpha stimulated the non-CF (NuLi-1) and CF (CuFi-1) bronchial wound healing rate. Surprisingly, chronic exposure to TNF-alpha enhanced this stimulation as well as the migration rate during repair. This wound healing rate stimulation by TNF-alpha seems to be due to metalloproteinase MMP-9 activation, EGF shedding by epithelial cells and subsequent EGFR transactivation. Furthermore, we recently reported a crucial relationship between the EGF response and K+ channel function, both controlling bronchial repair. We now show that TNF-alpha wound healing stimulation also implicated KvLQT1 and KATP currents activation. In contrast to its effect on cell migration, TNF-alpha downregulate cell proliferation. Thus, in addition to its recognized role in the inflammatory response leading to epithelial injury, TNF-a could exert complex actions on repair mechanisms of CF airway epithelia by upregulating cell migration while downregulating proliferation.
Inflammation EGFR MMP Airways Potassium channels