RT Journal Article
SR Electronic
T1 Cystic fibrosis epithelial cells are primed for apoptosis as a result of increased Fas
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 4739
VO 40
IS Suppl 56
A1 Sinéad Weldon
A1 Qiwei Chen
A1 Irene Oglesby
A1 Christine Wohlford-Lenane
A1 Jennifer Bartlett
A1 Gerry McElvaney
A1 Stuart Elborn
A1 Paul McCray, Jr
A1 Catherine Greene
A1 Clifford Taggart
YR 2012
UL http://erj.ersjournals.com/content/40/Suppl_56/4739.abstract
AB Apoptosis is a physiological process essential for homeostasis of epithelial organisation and function. Cystic fibrosis (CF) lung disease is characterised by chronic infection and inflammation and previous work suggests that apoptosis is dysfunctional in the CF airways with conflicting results. In addition, controversy exists regarding how CFTR misfolding contributes to apoptosis. In this study, we evaluated the relationship between CFTR mutation and apoptosis in CF airway epithelial cells. Basal activity of the executioner caspase, caspase-3, was significantly increased in CF tracheal and bronchial epithelial cell lines and primary bronchial epithelial cells compared to non-CF controls. In addition, activity of the upstream initiator caspase, caspase-8, was significantly increased in CF epithelial cells compared to controls, suggesting involvement of extrinsic apoptosis signalling, which is mediated by the activation of death receptors, such as Fas (CD95). Increased levels of Fas were observed in CF epithelial cells and bronchial brushings, reciprocal decreases in a selection of microRNAs predicted to target Fas were evident in the brushing samples, and neutralization of Fas significantly inhibited caspase-3 activity in CF epithelial cells compared to untreated cells. Furthermore, activation of Fas significantly increased caspase-3 activity and apoptosis in CF epithelial cells compared to control cells. Overall, these results suggest that CF airway epithelial cells are more sensitive to apoptosis via increased levels of Fas and subsequent activation of the Fas death receptor pathway. Further work will delineate the mechanism underlying increased Fas expression in CF epithelial cells.