title: Role of epidermal growth factor receptor in maintaining airway goblet cell hyperplasia in rats sensitized to allergen.
abstract: BACKGROUND
  Stimulation of epidermal growth factor receptor (EGFR) induces airway goblet cell hyperplasia, but the role of this molecule in the maintenance of this pathologic change remains uncertain.
  
  
  OBJECTIVE
  To determine the mechanisms by which goblet cell hyperplasia is maintained in airway epithelium, we investigated EGFR-induced signalling pathways that lead to both mucin production and antiapoptosis in vitro. We also tested whether the inhibition of EGFR tyrosine kinase speeds reversal of established goblet cell hyperplasia to normal epithelial phenotype in vivo.
  
  
  METHODS
  MUC5AC production was measured by immunoassay, and antiapoptotic responses were determined by Bcl-2 expression and terminal deoxynucleotidyl transferase-mediated dUTP-biotin Nick End Labelling staining using NCI-H292 cells. The effect of an inhibitor of EGFR tyrosine kinase (AG1478) on goblet cell hyperplasia was also determined in rats sensitized with ovalbumin (OVA).
  
  
  RESULTS
  MUC5AC was constitutively expressed and few apoptotic cells were observed in NCI-H292 cells under non-stimulated condition. TGF-alpha increased MUC5AC and Bcl-2 expression, an effect that was prevented by inhibitors of EGFR tyrosine kinase (AG1478), MEK (PD98059), and NF-kappaB (CAPE). After the addition of TGF-alpha, AG1478 and an inhibitor of phosphatidylinositol 3 kinase/Akt (LY294002), but not PD98059, induced a marked apoptotic response, which was prevented by the caspase inhibitor Z-VAD fmk. Goblet cell hyperplasia and EGFR expression in airway epithelium were noted in the OVA-sensitized rats. Intratracheal instillation of AG1478 induced apoptosis of goblet cells, reverting the airway epithelium to normal epithelial phenotype.
  
  
  CONCLUSIONS
  These findings indicate that EGFR plays an important role in the maintenance of goblet cell hyperplasia. We speculate that inhibitors of the EGFR cascade might be an effective therapy of airway remodelling.
authors.affiliation: First Department of Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Takeyama
authors.forename: J
authors.initials: J
authors.lastname: Tamaoki
authors.forename: M
authors.initials: M
authors.lastname: Kondo
authors.forename: K
authors.initials: K
authors.lastname: Isono
authors.forename: A
authors.initials: A
authors.lastname: Nagai
mesh_terms: D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004848:Epithelium / Q000473:pathology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020397:Goblet Cells / Q000473:pathology*; D006965:Hyperplasia / Q000473:pathology*; D008168:Lung / Q000166:cytology / Q000473:pathology*; D008297:Male; D055271:Mucin 5AC; D009077:Mucins / Q000096:biosynthesis; D010047:Ovalbumin / Q000008:administration & dosage*; D051381:Rats; D011914:Rats, Inbred BN; D015398:Signal Transduction
chemical_list: D000485:Allergens; D004791:Enzyme Inhibitors; C524680:Muc5ac protein, rat; D055271:Mucin 5AC; D009077:Mucins; D010047:Ovalbumin; D066246:ErbB Receptors