Pivotal role of PAI-1 in a murine model of hepatic vein thrombosis
Pivotal role of PAI-1 in a murine model of hepatic vein thrombosis
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DOI：
10.1182/blood-2005-07-2681
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发表时间：
2006-01-01
期刊：
影响因子：
20.3
通讯作者：
Vaughan, DE
中科院分区：
文献类型：
--
作者：
Smith, LH;Dixon, JD;Vaughan, DE
肝静脉闭塞病（VOD）是骨髓移植大剂量化疗的常见并发症。虽然VOID的发病机制尚不确定，但纤溶酶原激活物抑制剂-1（派-1）已成为人类VOID的诊断标志物和预测因子。在这项研究中，我们研究了派-1在VOD小鼠模型中的作用，该模型是通过使用L-NAME长期抑制一氧化氮合酶产生的。6周后，野生型（WT）小鼠出现广泛的纤维素样肝静脉血栓和肝损伤和功能障碍的生化证据。相比之下，派-1缺陷型小鼠在很大程度上免受肝静脉血栓形成的发展。此外，野生型小鼠接受tiplaxtinin，派-1的拮抗剂，有效地保护从L-NAME诱导的血栓形成。总之，这些数据表明，NO和派-1在肝静脉血栓形成中起关键和拮抗作用，派-1是预防和治疗人类VOID的潜在靶点。
Hepatic veno-occlusive disease (VOD) is a common complication of high-dose chemotherapy associated with bone marrow transplantation. While the pathogenesis of VOID is uncertain, plasminogen activator inhibitor-1 (PAI-1) has emerged as a diagnostic marker and predictor of VOID in humans. In this study, we investigated the role of PAI-1 in a murine model of VOD produced by long-term nitric oxide synthase inhibition using L-NAME. After 6 weeks, wild-type (WT) mice developed extensive fibrinoid hepatic venous thrombi and biochemical evidence of hepatic injury and dysfunction. In contrast, PAI-1-deficient mice were largely protected from the development of hepatic vein thrombosis. Furthermore, WT mice that received tiplaxtinin, an antagonist of PAI-1, were effectively protected from L-NAME-induced thrombosis. Taken together, these data indicate that NO and PAI-1 play pivotal and antagonistic roles in hepatic vein thrombosis and that PAI-1 is a potential target in the prevention and treatment of VOID in humans.