Abstract
Introduction: Despite the broad anti-inflammatory effects of glucocorticoids (GC), they provide little therapeutic benefit in COPD. Mitochondrial dysfunction has been described in COPD patients and can be induced in airway epithelial cells in vitro by cigarette smoke. We hypothesize that impaired mitochondrial function induces a phenotypic shift in airway epithelial cells leading to increased pro-inflammatory responses, impaired barrier function and reduced GC sensitivity.
Methods: We determined IL-8 secretion (ELISA) and epithelial barrier function (ECIS) in the alveolar epithelial cell line A549 and the mitochondrial impaired cell line A549.B2 and their sensitivity to the GC budesonide (10-8M).
Results: Basal production of IL-8 by mitochondrially impaired A549.B2 cells is increased compared to A549 control cells. Moreover, suppression of IL-8 by the GC budesonide (10-8M) is significantly less (24%±9%, p<0.02) in A549.B2 cells compared to A549 cells. Furthermore, while budesonide was able to efficiently increase barrier function in control A549 cells (p<0.001), there was not significant effect in A549.B2 cells. Finally, we observed that A549.B2 cells were less capable to recover from wounding than control A549 cells.
Conclusion/Discussion: In conclusion, our data indicate that mitochondrial dysfunction leads to increased pro-inflammatory activity, inefficient wound healing and reduced responsiveness to GCs. We speculate that mitochondrial dysfunction as observed in COPD may contribute to the GC-insensitive chronic airway inflammation in this disease.
- © 2011 ERS