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Published ahead of print on September 18, 2003, doi:10.1165/rcmb.2003-0199OC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 4, April 2004, 470-478

A more recent version of this article appeared on April 1, 2004
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Submitted on May 27, 2003
Revised on September 16, 2003

Human airway trypsin-like protease increases mucin gene expression in airway epithelial cells

Manabu Chokki1*, Satoshi Yamamura1, Hiroshi Eguchi1, Tsukio Masegi1, Hideki Horiuchi1, Hirofumi Tanabe1, Takashi Kamimura1, and Susumu Yasuoka2

1 Pharmacological Research, Teijin Institute for Bio-Medical Research, Tokyo, Japan, 2 Nutrition, University of Tokushima School of Medicine, Tokushima, Japan

* To whom correspondence should be addressed. E-mail: m.chiyotsuki{at}teijin.co.jp.

HAT (human airway trypsin-like protease) 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-EGFR (anti-epidermal growth factor receptor) -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.




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