Effect of MMP/ADAM inhibitors on goblet cell hyperplasia in cultured human bronchial epithelial cells.
While epidermal growth factor receptor (EGFR) plays a pivotal role in the repair process of epithelial cells, it is also involved in the overproduction of mucus and goblet cell hyperplasia (GCH), which occurs in chronic airway diseases such as asthma. Among the EGFR ligands, transforming growth factor (TGF)-alpha is thought to be the most important in the synthesis of mucus. Pro-TGF-alpha is cleaved to give an active form by members of the matrix metalloproteinases (MMP)/a disintegrin and metalloproteinases (ADAM) family. Thus MMP/ADAM inhibitors might prevent GCH by inhibiting transactivation of EGFR. Upon stimulation of differentiating normal human bronchial epithelial (NHBE) cells by IL-13, GCH was induced. The mucin genes MUC5AC, MUC5B, and MUC2 were upregulated whereas the expression of ciliated cell markers was greatly repressed. GM6001, a broad-spectrum inhibitor for MMP/ADAM, inhibited IL-13-induced mucin gene expression and mucus production as measured by periodic acid-Schiff staining. This was accompanied by an inhibition of TGF-alpha release. These results suggest that MMP/ADAMs play a pivotal role in the development of GCH in lung epithelial cells.
Yoshisue
Hajime
H
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Sunto, Shizuoka 411-8731, Japan. hyoshisu@soton.ac.uk
Hasegawa
Kazuhide
K
D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D020397:Goblet Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy* / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055271:Mucin 5AC; D055257:Mucin-5B; D009077:Mucins / Q000378:metabolism; D009093:Mucus; D012394:Rosaniline Dyes / Q000737:chemistry; D016211:Transforming Growth Factor alpha / Q000378:metabolism
D004151:Dipeptides; D004791:Enzyme Inhibitors; D018793:Interleukin-13; C524678:MUC5AC protein, human; C524578:MUC5B protein, human; D055271:Mucin 5AC; D055257:Mucin-5B; D009077:Mucins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D012394:Rosaniline Dyes; C476677:Schiff's reagent; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors; D008666:Metalloendopeptidases