Smith Layton H, Dixon John D, Stringham John R, Eren Mesut, Elokdah Hassan, Crandall Dave L, Washington Kay, Vaughan Douglas E
Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2220 Pierce Ave, Nashville, TN 37232, USA.
Blood. 2006 Jan 1;107(1):132-4. doi: 10.1182/blood-2005-07-2681. Epub 2005 Sep 13.
Hepatic veno-occlusive disease (VOD) is a common complication of high-dose chemotherapy associated with bone marrow transplantation. While the pathogenesis of VOD is uncertain, plasminogen activator inhibitor-1 (PAI-1) has emerged as a diagnostic marker and predictor of VOD 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 VOD in humans.
肝静脉闭塞病（VOD）是与骨髓移植相关的高剂量化疗的常见并发症。虽然VOD的发病机制尚不清楚，但纤溶酶原激活物抑制剂-1（PAI-1）已成为人类VOD的诊断标志物和预测指标。在本研究中，我们使用L-NAME长期抑制一氧化氮合酶，研究了PAI-1在VOD小鼠模型中的作用。6周后，野生型（WT）小鼠出现广泛的纤维蛋白样肝静脉血栓形成以及肝损伤和功能障碍的生化证据。相比之下，PAI-1缺陷小鼠在很大程度上免受肝静脉血栓形成的影响。此外，接受PAI-1拮抗剂替普拉西丁的WT小鼠有效地免受L-NAME诱导的血栓形成。综上所述，这些数据表明NO和PAI-1在肝静脉血栓形成中起关键和拮抗作用，并且PAI-1是人类VOD预防和治疗的潜在靶点。
