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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Role of Chymase-Dependent Matrix Metalloproteinase-9 Activation in Mice with Dextran Sodium Sulfate-Induced Colitis

Second Department of Internal Medicine (K.I., M.Mu., T.N., T.I., N.M., E.U., K.H.) and Department of Pharmacology (S.T., N.I., D.J., M.Mi.), Osaka Medical College, Takatsuki City, Osaka, Japan

Matrix metalloproteinase (MMP)-9 plays an important role in the pathogenesis of colitis. Recent studies have demonstrated that chymase is involved in the conversion of promatrix metalloproteinase (proMMP)-9 to MMP-9. However, whether chymase contributes to the activation of proMMP-9 in colitis has remained unclear. In this study, we administered 5% dextran sodium sulfate (DSS) solution to mice for 7 days. At 7 days after starting administration, both chymase activity and MMP-9 activity were significantly increased. In extract from colitis in DSS-treated mice, MMP-9 activity was significantly increased after 8 h of incubation, but increased activity was almost completely suppressed in the presence of a chymase inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[{3,4-dioxo-1-phenyl-7-(2-pyridyloxy)}-2-heptyl] acetamide (NK3201). At 7 days after starting administration, intestinal length was significantly shorter in DSS-treated mice than in normal mice, but these changes were significantly prevented by NK3201 (10 mg/kg per day i.p.). Disease activity index and histological damage score were also significantly reduced by NK3201. The filtrated neutrophil number was significantly decreased by NK3201. Furthermore, NK3201 significantly attenuated not only chymase activity but also MMP-9 activity in DSS-treated mice. These findings suggest that chymase plays an important role in the development of colitis via MMP-9 activation.

Address correspondence to: Dr. Shinji Takai, Department of Pharmacology, Osaka Medical College, Takatsuki City, Osaka 569-8686, Japan. E-mail: pha010{at}art.osaka-med.ac.jp

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