Sinusoidal obstruction syndrome (veno-occlusive disease) in the rat is prevented by matrix metalloproteinase inhibition
Sinusoidal obstruction syndrome (veno-occlusive disease) in the rat is prevented by matrix metalloproteinase inhibition
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DOI：
10.1016/s0016-5085(03)01056-4
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发表时间：
2003-09-01
期刊：
影响因子：
29.4
通讯作者：
Tokes, ZA
中科院分区：
文献类型：
--
作者：
DeLeve, LD;Wang, XD;Tokes, ZA
背景和目的：正窦阻塞综合征中阻塞的机械起源是由迪斯间隙的正弦内皮细胞裂开引发的。研究了导致窦状内皮细胞裂开的生化变化。方法：体外和体内研究检查了野百合碱（一种吡咯里西啶生物碱）引起的变化，可在人类和实验动物中诱发肝窦阻塞综合征。结果：在野百合碱诱导的肝窦阻塞综合征大鼠模型中，肝脏中基质金属蛋白酶-9早期升高，随后基质金属蛋白酶-2升高幅度较小。肝窦内皮细胞、肝细胞、星状细胞和库普弗细胞的体外研究表明，肝窦内皮细胞是基础和野百合碱诱导的基质金属蛋白酶-9/基质金属蛋白酶-2活性的主要来源。野百合碱引起窦内皮细胞中 F-肌动蛋白解聚，阻断 F-肌动蛋白解聚可阻止基质金属蛋白酶活性的增加。基质金属蛋白酶抑制剂的施用可预防与肝窦阻塞综合征相关的体征和组织学变化。结论：野百合碱引起肝窦内皮细胞中F-肌动蛋白解聚，导致肝窦内皮细胞金属蛋白酶9和基质金属蛋白酶2表达增加。抑制基质金属蛋白酶 9 和基质金属蛋白酶 2 可防止窦窦阻塞综合征的发生，表明基质金属蛋白酶抑制剂可能是一种治疗上可行的预防策略。
Background & Aims: The mechanical origins of the obstruction in sinusoidal obstruction syndrome are initiated by dehiscence of sinusoidal endothelial cells from the space of Disse. The biochemical changes that permit the dehiscence of the sinusoidal endothelial cells were investigated. Methods: In vitro and in vivo studies examined changes induced by monocrotaline, a pyrrolizidine alkaloid that induces sinusoidal obstruction syndrome in both humans and experimental animals. Results: In the monocrotaline-induced rat model of sinusoidal obstruction syndrome, there was an early increase of matrix metalloproteinase-9 and a later, lower-magnitude increase of matrix metalloproteinase-2 in the liver. In vitro studies of sinusoidal endothelial cells, hepatocytes, stellate cells, and Kupffer cells showed that sinusoidal endothelial cells are the major source of both basal and monocrotaline-induced matrix metalloproteinase-9/matrix metalloproteinase-2 activity. Monocrotaline caused depolymerization of F-actin in sinusoidal endothelial cells, and blocking of F-actin depolymerization prevented the increase in matrix metalloproteinase activity. Administration of matrix metalloproteinase inhibitors prevented the signs and histological changes associated with sinusoidal obstruction syndrome. Conclusions: Monocrotaline causes depolymerization of F-actin in sinusoidal endothelial cells, which leads to increased expression of metalloproteinase-9 and matrix metalloproteinase-2 by sinusoidal endothelial cells. Inhibition of matrix metalloproteinase-9 and matrix metalloproteinase-2 prevents the development of sinusoidal obstruction syndrome, establishing that matrix metalloproteinase inhibitors may be a therapeutically viable strategy for prevention.