RT Journal Article
SR Electronic
T1 Cigarette smoke impairs airway epithelial barrier function and cell-cell contact recovery
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP erj01938-2010
DO 10.1183/09031936.00193810
A1 I.H. Heijink
A1 S.M. Brandenburg
A1 D.S. Postma
A1 A.J.M. van Oosterhout
YR 2011
UL http://erj.ersjournals.com/content/early/2011/07/12/09031936.00193810.abstract
AB Cigarette smoking, the major cause of COPD, induces aberrant airway epithelial structure and function. The underlying mechanisms are unresolved so far.We studied effects of cigarette smoke extract (CSE) on epithelial barrier function and wound regeneration in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBEC) from COPD patients, non-smokers and healthy smokers.We demonstrate that CSE rapidly and transiently impairs 16HBE barrier function, largely due to disruption of cell-cell contacts. CSE induced a similar, but stronger and more sustained defect in PBEC. Application of the specific EGFR-inhibitor AG1478 showed that EGFR activation contributes to the CSE-induced defects in both 16HBE and PBEC. Furthermore, our data indicate that the endogenous protease calpain mediates these defects through tight junction protein degradation. CSE also delayed the reconstitution of 16HBE intercellular contacts during wound healing and attenuated PBEC barrier function upon wound regeneration. These findings were comparable between PBEC from smokers, healthy smokers and COPD patients.In conclusion, we demonstrate for the first time that CSE reduces epithelial integrity, likely by EGFR and calpain-dependent disruption of intercellular contacts. This may increase susceptibility to environmental insults, e.g. inhaled pathogens. Thus, EGFR may be a promising target for therapeutic strategies to improve mucosal barrier function in cigarette smoking-related disease.