Published ahead of print on January 19, 2006, doi:10.1165/rcmb.2005-0386OC
Am. J. Respir. Cell Mol. Biol., Volume 34, Number 5, May 2006, 581-591
A more recent version of this article appeared on May 1, 2006
Submitted on October 14, 2005
Revised on January 18, 2006
EGFR Activation by EGF Mediates Oxidant-induced Goblet Cell Metaplasia in Human Airway Epithelium
Susana M Casalino-Matsuda1, Maria E Monzon1, and Rosanna M Forteza1*
1 Division of Pulmonary and Critical Care Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA
* To whom correspondence should be addressed. E-mail: rforteza{at}miami.edu.
Mucus overproduction in inflammatory and obstructive airway diseases is associated with goblet cell (GC) metaplasia in airways. Although the mechanisms involved in GC metaplasia and mucus hypersecretion are not completely understood, association with oxidative stress and epidermal growth factor receptor (EGFR) signaling has been reported. To explore the mechanisms involved in oxidative stress-induced GC metaplasia, cultures of differentiated normal human bronchial epithelial (NHBE) cells grown at the air liquid interface (ALI) were exposed to reactive oxygen species (ROS) generated by xanthine/xanthine oxidase (X/XO). EGFR activation and signaling was assessed by measuring EGF and TGF- release and EGFR and 44/42MAPK phosphorylation. The GC population was evaluated by confocal microscopy. ROS-induced EGFR activation resulted in GC proliferation and increased MUC5AC gene and protein expression. Signaling was due to pro-EGF processing by tissue kallikrein (TK) that in turn was activated by ROS-induced hyaluronan breakdown. It was inhibited by catalase, a TK inhibitor and EGF blocking antibodies. Exposure to rTK mimicked the ROS effects increasing the expression of MUC5AC and lactoperoxidase (LPO). In addition, ROS induced the antiapoptotic factor Bcl-2 in a TK-dependent fashion. In conclusion, ROS-induced GC metaplasia in NHBE cells is associated with HA depolymerization and EGF processing by TK followed by EGFR signaling, suggesting that increases in TK activity could contribute, at least in part, to GC metaplasia and mucus hypersecretion in diseases such as asthma and chronic bronchitis. The data also suggest that increases in GC population could be sustained by the associated up-regulation of Bcl-2 in airway epithelial cells.
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