コンドウ　ミツコ   Kondou Mitsuko   近藤　光子    所属   医学部 医学科（東京女子医科大学病院）    職種   特任教授
論文種別	原著
言語種別	英語
査読の有無	査読なし
表題	Role of epidermal growth factor receptor in maintaining airway goblet cell hyperplasia in rats sensitized to allergen.
掲載誌名	正式名：Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 略　 称：Clin Exp Allergy ISSNコード：1365-2222(Electronic)0954-7894(Linking)
巻・号・頁	38(5),pp.857-65
著者・共著者	Takeyama K, Tamaoki J, Kondo M, Isono K, Nagai A
発行年月	2008/05
概要	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.CONCLUSION: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.
DOI	10.1111/j.1365-2222.2008.02951.x
文献番号	18307528