Schultze A E, Roth R A
Department of Pathology, Michigan State University, East Lansing 48824.
Toxicol Appl Pharmacol. 1993 Jul;121(1):129-37. doi: 10.1006/taap.1993.1137.
Monocrotaline pyrrole (MCTP), a putative toxic metabolite of the pyrrolizidine alkaloid, monocrotaline, causes pulmonary vascular thrombi that are associated with vascular remodeling, pulmonary hypertension, and right cardioventricular hypertrophy in rats. It is possible that such thrombi contribute to the lung injury and pulmonary hypertension in this model. A previous study indicated that rats treated with MCTP did not have excessive procoagulant activity in the peripheral blood. Since thrombosis may also result from insufficient fibrinolytic activity in the systemic circulation, we evaluated the fibrinolytic system of rats given MCTP. Male Sprague-Dawley rats were given a single injection of MCTP (3.5 mg/kg) or an equal volume of N,N-dimethylformamide vehicle in the tail vein and were killed at 1, 3, 5, 8, 11, or 14 days after toxin administration. Several markers of lung injury and fibrinolysis were measured. Lung injury was evident 3 days after administration of MCTP and became more pronounced with time. In MCTP-treated rats, right heart hypertrophy was observed at 11 days and became more pronounced at 14 days. There was no change in the plasminogen concentration or in the activities of tissue plasminogen activator or alpha 2-antiplasmin in blood throughout the time course. Beginning at Day 8 and continuing through Day 14, there was an increase in the activity of plasminogen activator inhibitor in blood of rats that received MCTP. In addition, we evaluated the fibrinolytic activity of lung tissue slices. Rats treated with MCTP had a significant decrease in fibrinolytic activity of lung tissue at Day 3. A more pronounced decrease was evident by Day 8, and this continued through Day 14. In summary, MCTP treatment of rats decreases the fibrinolytic activity of lung tissue relatively early after exposure to the toxicant and before the onset of pulmonary hypertension. The change is reflected slightly later in plasma. These alterations in fibrinolytic activity may explain why fibrin thrombi form in the lungs of rats treated with MCTP.
单猪屎豆碱吡咯（MCTP）是吡咯里西啶生物碱单猪屎豆碱的一种潜在有毒代谢产物，可导致大鼠肺血管血栓形成，这些血栓与血管重塑、肺动脉高压和右心室肥大有关。在该模型中，此类血栓可能导致肺损伤和肺动脉高压。先前的一项研究表明，用MCTP处理的大鼠外周血中没有过度的促凝活性。由于血栓形成也可能是由于全身循环中纤维蛋白溶解活性不足所致，我们评估了给予MCTP的大鼠的纤维蛋白溶解系统。将雄性Sprague-Dawley大鼠尾静脉单次注射MCTP（3.5mg/kg）或等体积的N，N-二甲基甲酰胺载体，并在给予毒素后1、3、5、8、11或14天处死。测量了肺损伤和纤维蛋白溶解的几个标志物。给予MCTP后3天肺损伤明显，且随时间推移变得更加明显。在MCTP处理的大鼠中，11天时观察到右心肥大，14天时变得更加明显。在整个时间过程中，血浆中纤溶酶原浓度、组织纤溶酶原激活物或α2-抗纤溶酶的活性均无变化。从第8天开始并持续到第14天，接受MCTP的大鼠血液中纤溶酶原激活物抑制剂的活性增加。此外，我们评估了肺组织切片 的纤维蛋白溶解活性。用MCTP处理的大鼠在第3天时肺组织的纤维蛋白溶解活性显著降低。到第8天时，更明显的降低变得明显，并且这种情况持续到第14天。总之，用MCTP处理大鼠在接触毒物后相对早期且在肺动脉高压发作之前降低了肺组织的纤维蛋白溶解活性。这种变化在血浆中稍晚反映出来。纤维蛋白溶解活性的这些改变可能解释了为什么在用MCTP处理的大鼠肺中形成纤维蛋白血栓。
