TY - JOUR
T1 - Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis
AU - Morohoshi, Yuichi
AU - Matsuoka, Katsuyoshi
AU - Chinen, Hiroshi
AU - Kamada, Nobuhiko
AU - Sato, Toshiro
AU - Hisamatsu, Tadakazu
AU - Okamoto, Susumu
AU - Inoue, Nagamu
AU - Takaishi, Hiromasa
AU - Ogata, Haruhiko
AU - Iwao, Yasushi
AU - Hibi, Toshifumi
PY - 2006/4
Y1 - 2006/4
N2 - Background: Neutrophil elastase (NE) is a major secretory product from activated neutrophils and a major contributor to tissue destruction. However, little is known about the pathogenic contribution of NE to ulcerative colitis (UC). This study was designed to investigate the contribution of NE by measuring NE activity in plasma and colonic mucosal tissue from UC patients and a murine acute colitis model, and to elucidate the therapeutic effect of the NE-specific inhibitor ONO-5046. Methods: The NE enzyme activities in plasma and colonic mucosal tissue from UC patients were directly measured using an enzyme-substrate reaction. Acute colitis was induced in mice by administration of 1.5% dextran sulfate sodium (DSS) for 5 days. DSS-induced colitis mice were then treated with ONO-5046 (50 mg/kg body weight) intraperitoneally twice a day. Results: In UC patients, the NE enzyme activity was significantly elevated in both the plasma and colonic mucosal tissue compared with healthy controls. In DSS-induced colitis mice, the NE enzyme activity increased in parallel with the disease development. ONO-5046 showed therapeutic effects in DSS-treated mice by significantly reducing weight loss and histological score. ONO-5046 suppressed the NE enzyme activities in both plasma and culture supernatant of colonic mucosa from DSS-induced colitis mice. Conclusions: ONO-5046, a specific NE inhibitor, prevented the development of DSS-induced colitis in mice. NE therefore represents a promising target for the treatment of UC patients.
AB - Background: Neutrophil elastase (NE) is a major secretory product from activated neutrophils and a major contributor to tissue destruction. However, little is known about the pathogenic contribution of NE to ulcerative colitis (UC). This study was designed to investigate the contribution of NE by measuring NE activity in plasma and colonic mucosal tissue from UC patients and a murine acute colitis model, and to elucidate the therapeutic effect of the NE-specific inhibitor ONO-5046. Methods: The NE enzyme activities in plasma and colonic mucosal tissue from UC patients were directly measured using an enzyme-substrate reaction. Acute colitis was induced in mice by administration of 1.5% dextran sulfate sodium (DSS) for 5 days. DSS-induced colitis mice were then treated with ONO-5046 (50 mg/kg body weight) intraperitoneally twice a day. Results: In UC patients, the NE enzyme activity was significantly elevated in both the plasma and colonic mucosal tissue compared with healthy controls. In DSS-induced colitis mice, the NE enzyme activity increased in parallel with the disease development. ONO-5046 showed therapeutic effects in DSS-treated mice by significantly reducing weight loss and histological score. ONO-5046 suppressed the NE enzyme activities in both plasma and culture supernatant of colonic mucosa from DSS-induced colitis mice. Conclusions: ONO-5046, a specific NE inhibitor, prevented the development of DSS-induced colitis in mice. NE therefore represents a promising target for the treatment of UC patients.
KW - Dextran sulfate sodium-induced colitis
KW - Neutrophil elastase
KW - ONO-5046
KW - Ulcerative colitis
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U2 - 10.1007/s00535-005-1768-8
DO - 10.1007/s00535-005-1768-8
M3 - Article
C2 - 16741610
AN - SCOPUS:33744806687
VL - 41
SP - 318
EP - 324
JO - Journal of Gastroenterology
JF - Journal of Gastroenterology
SN - 0944-1174
IS - 4
ER -