title: Chymase inhibition attenuates monocrotaline-induced sinusoidal obstruction syndrome in hamsters.
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.
authors.affiliation: Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki 569-8686, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Masubuchi
authors.forename: K
authors.initials: K
authors.lastname: Komeda
authors.forename: S
authors.initials: S
authors.lastname: Takai
authors.forename: D
authors.initials: D
authors.lastname: Jin
authors.forename: K
authors.initials: K
authors.lastname: Tashiro
authors.forename: Zhong-Lian
authors.initials: ZL
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Otsuki
authors.forename: H
authors.initials: H
authors.lastname: Okamura
authors.forename: M
authors.initials: M
authors.lastname: Hayashi
authors.forename: K
authors.initials: K
authors.lastname: Uchiyama
mesh_terms: D000818:Animals; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D016686:Monocrotaline / Q000008:administration & dosage; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D013449:Sulfonamides; C524344:TY 51469; D013876:Thiophenes; D016686:Monocrotaline; D053818:Chymases