Title:Chymase Inhibition Attenuates Monocrotaline-Induced Sinusoidal Obstruction Syndrome in Hamsters
Volume: 20
Issue: 21
Author(s): S. Masubuchi, K. Komeda, S. Takai, D. Jin, K. Tashiro, Zhong-Lian Li, Y. Otsuki, H. Okamura, M. Hayashi and K. Uchiyama
Affiliation:
Keywords:
Chymase, inhibitor, mast cells, matrix metalloproteinase-9, myeloperoxidase, sinusoidal obstruction syndrome,
tumor necrosis factor-α.
Abstract: 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.
