title: Epidermal growth factor receptor activation by epidermal growth factor mediates oxidant-induced goblet cell metaplasia in human airway epithelium.
abstract: 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 (44/42)MAPK 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine (R-47), University of Miami School of Medicine, 1600 NW 10th Ave, RMSB 7072A, Miami, FL 33136, USA. mmatsuda@med.miami.edu
authors.forename: S Marina
authors.initials: SM
authors.lastname: Casalino-Matsuda
authors.forename: Maria E
authors.initials: ME
authors.lastname: Monzón
authors.forename: Rosanna M
authors.initials: RM
authors.lastname: Forteza
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D020397:Goblet Cells / Q000166:cytology / Q000187:drug effects* / Q000473:pathology*; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D007784:Lactoperoxidase / Q000378:metabolism; D008679:Metaplasia; D055271:Mucin 5AC; D009077:Mucins / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress; D011108:Polymers; D011498:Protein Precursors / Q000378:metabolism; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D020840:Tissue Kallikreins / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009077:Mucins; D016877:Oxidants; D011108:Polymers; D011498:Protein Precursors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C042652:epidermal growth factor precursor; D004815:Epidermal Growth Factor; D006820:Hyaluronic Acid; D007784:Lactoperoxidase; D014969:Xanthine Oxidase; D066246:ErbB Receptors; D020840:Tissue Kallikreins