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Published ahead of print on January 19, 2006, doi:10.1165/rcmb.2005-0386OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 34, pp. 581-591, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2005-0386OC

Epidermal Growth Factor Receptor Activation by Epidermal Growth Factor Mediates Oxidant-Induced Goblet Cell Metaplasia in Human Airway Epithelium

S. Marina Casalino-Matsuda, Maria E. Monzón and Rosanna M. Forteza

Division of Pulmonary and Critical Care Medicine, University of Miami, Miller School of Medicine, Miami, Florida

Correspondence and requests for reprints should be addressed to Rosanna M. Forteza, M.D., and S. Marina Casalino-Matsuda, Ph.D., Division of Pulmonary and Critical Care Medicine (R-47), University of Miami School of Medicine, 1600 NW 10th Ave, RMSB 7072A, Miami, FL 33136. E-mail: rforteza{at}miami.edu or mmatsuda{at}med.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 cells grown at the air–liquid interface were exposed to reactive oxygen species (ROS) generated by xanthine/xanthine oxidase. EGFR activation and signaling was assessed by measuring EGF and transforming growth factor-{alpha} 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), which was activated by ROS-induced hyaluronan breakdown. It was inhibited by catalase, a TK inhibitor, and EGF-blocking antibodies. Exposure to recombinant TK mimicked the ROS effects, increasing the expression of MUC5AC and lactoperoxidase. In addition, ROS induced the antiapoptotic factor Bcl-2 in a TK-dependent fashion. In conclusion, ROS-induced GC metaplasia in normal human bronchial epithelial cells is associated with HA depolymerization and EGF processing by TK followed by EGFR signaling, suggesting that increases in TK activity could contribute 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 upregulation of Bcl-2 in airway epithelial cells.

Key Words: EGFR • goblet cells • hyaluronan • NHBE cells • tissue kallikrein




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