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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Chymase Inhibition Attenuates Monocrotaline-Induced Sinusoidal Obstruction Syndrome in Hamsters

Author(s): S. Masubuchi, K. Komeda, S. Takai, D. Jin, K. Tashiro, Zhong-Lian Li, Y. Otsuki, H. Okamura, M. Hayashi and K. Uchiyama

Volume 20 , Issue 21 , 2013

Page: [2723 - 2729] Pages: 7

DOI: 10.2174/0929867311320210008

Price: $65


Chymase stored in mast cells activates matrix metalloproteinase (MMP)-9, which may relate to the progression of sinusoidal obstruction syndrome (SOS). We investigated the preventive effect of a chymase inhibitor, TY-51469, on monocrotaline-induced SOS in hamsters. Hamsters were orally administrated with a single dose of monocrotaline (120 mg/kg) to induce SOS. Treatment with TY-51469 (1 mg/kg per day) or placebo had started 3 days before the monocrotaline administration. Two days after the monocrotaline administration, significant increases in aspartate aminotransferase, alanine aminotransferase and total bilirubin and a significant reduction of albumin were observed in plasma, but their changes were significantly attenuated by treatment with TY-51469. The numerous hepatic necrosis areas were observed in the placebo-treated group, but the ratio of necrotic area to total area in liver had been significantly reduced by treatment with TY-51469. Both chymase activity and MMP-9 level in liver were significantly augmented in the placebo-treated group. Furthermore, tumor necrosis factor (TNF)-α level in liver was also augmented in the placebo-treated group. However, the chymase activity and levels of MMP-9 and TNF-α were significantly attenuated in the TY-51469-treated group. Until 14 days after monocrotaline administration, survival rates in the placebo- and TY-51469-treated groups were 25% and 70%, respectively, and a significant difference was observed. In conclusion, chymase inhibition by TY-51469 may prevent the accelerating of severity in monocrotaline-induced SOS in hamsters.

Keywords: Chymase, inhibitor, mast cells, matrix metalloproteinase-9, myeloperoxidase, sinusoidal obstruction syndrome, tumor necrosis factor-α.

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