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Published ahead of print on September 18, 2003, doi:10.1165/rcmb.2003-0199OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 30, pp. 470-478, 2004
© 2004 American Thoracic Society
DOI: 10.1165/rcmb.2003-0199OC

Human Airway Trypsin-Like Protease Increases Mucin Gene Expression in Airway Epithelial Cells

Manabu Chokki, Satoshi Yamamura, Hiroshi Eguchi, Tsukio Masegi, Hideki Horiuchi, Hirofumi Tanabe, Takashi Kamimura and Susumu Yasuoka

Pharmacological Research Department, Teijin Institute for Bio-Medical Research, Teijin Limited, Tokyo; and Department of Nutrition, University of Tokushima School of Medicine, Tokushima City, Japan

Address correspondence to: Manabu Chokki, Pharmacological Research Department, Teijin Institute for Bio-Medical Research, Tokyo 191–8512, Japan. E-mail: m.chiyotsuki{at}teijin.co.jp

Human airway trypsin-like protease (HAT) is a serine protease found in sputum of patients with chronic airway diseases and is an agonist of protease-activated receptor-2 (PAR-2). Results from this study show that HAT treatment also enhances mucus production by the airway epithelial cell line NCI-H292 in vitro. Histologic examination showed that HAT enhances mucous glycoconjugate synthesis, whereas the PAR-2 agonist peptide (PAR-2 AP) has no such effect. HAT, but not PAR-2 AP, enhances MUC2 and MUC5AC gene expression 23-fold and 32-fold, respectively. The proteolytic activity of HAT is required to enhance MUC5AC gene expression; the addition of the inhibitors of trypsin-like protease activity of HAT, aprotinin and leupeptin, abolishes its enhancing effect. AG1478, anti-epidermal growth factor receptor (anti-EGFR)–neutralizing antibody, and anti-amphiregulin (AR)-neutralizing antibody all inhibited the stimulatory effect of HAT. Furthermore, HAT increases AR gene expression and subsequent AR protein release, whereas PAR-2 AP shows no such effects. These results indicate that HAT enhances mucin gene expression through an AR-EGFR pathway, and PAR-2 is not sufficient for or does not directly cause HAT-induced mucin gene expression. Thus, HAT might be a possible therapeutic target to prevent excessive mucus production in patients with chronic airway diseases.

Abbreviations: Alcian Blue and periodic acid-Schiff, AB-PAS • amphiregulin, AR • epidermal growth factor, EGF • epidermal growth factor receptor, EGFR • enzyme-linked immunosorbent assay, ELISA • human airway trypsin-like protease, HAT • heparin-binding EGF-like growth factor, HB-EGF • protease-activated receptor, PAR • PAR-2 agonist peptide, PAR-2 AP • heterotrimeric guanine nucleotide-binding protein, G-protein • reverse transcription–polymerase chain reaction, RT-PCR • serum-free medium, SFM • transforming growth factor-{alpha}, TGF-{alpha}




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