Plasmin inhibition increases MMP-9 activity and decreases vein wall stiffness during venous thrombosis resolution
Plasmin inhibition increases MMP-9 activity and decreases vein wall stiffness during venous thrombosis resolution
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DOI：
10.1016/j.jss.2007.03.064
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发表时间：
2007-10-01
影响因子：
2.2
通讯作者：
Henke, Peter K.
中科院分区：
文献类型：
--
作者：
Dewyer, Nicholas A.;Sood, Vikram;Henke, Peter K.
导言。深静脉血栓形成(DVT)的解决涉及到纤溶酶和基质金属蛋白酶(MMP)系统。本研究验证了药物抑制纤溶酶系统将损害DVT的分辨率并加重静脉壁损害的假说。结扎下腔静脉(IVC)建立大鼠下腔静脉血栓形成模型，术后7d静脉注射生理盐水或抑肽酶(AP，2.8 mg/kg)，取下腔静脉血栓。激光多普勒成像后，分离和称量DVT，并用张力计评估静脉壁硬度。血栓和静脉壁组织分析采用比色法测定总胶原，细胞因子、趋化因子、D-二聚体测定采用ELISA法，尿激酶-纤溶酶原激活物(UPA)和纤溶酶原激活物抑制物(PAI-1)采用免疫印迹法，NMP-2和-9采用酶谱法，中性粒细胞(PMN)和单核细胞(ED-1)采用免疫组织化学方法。AP治疗的大鼠的DVT重量增加了2倍(P<；0.05)，但在血栓灌注量、胶原或D-二聚体水平方面没有发现显著差异。静脉壁硬度降低了50%(P<；0.05)，表明生物力学损伤较小。AP组静脉壁总基质金属蛋白酶-9较对照组增加5倍(P<；0.05)，而基质金属蛋白酶-2虽升高，但无统计学意义。静脉壁肿瘤坏死因子-α、组织生长因子-β、静脉壁或血栓单核细胞、中性粒细胞、uPA/PAI-1比值两组间差异无统计学意义。AP对纤溶酶系统的抑制与较大的血栓和较少的静脉壁损伤有关，但在其他分辨率指标上没有差异，可能是因为静脉壁基质金属蛋白酶-9活性增加。这些数据表明了DVT解决的一个重要的冗余机制。(C)2007 Elsevier Inc.保留所有权利。
Introduction. Deep venous thrombosis (DVT) resolution involves the plasmin and the matrix metalloproteinase (MMP) system. This study tested the hypothesis that pharmacological inhibition of the plasmin system would impair DVT resolution and worsen vein wall damage.Methods. A rat model of stasis DVT by inferior vena cava (IVC) ligation was performed with intravenous control saline or aprotinin (AP; 2.8 mg/kg at operation), and harvest of thrombosed IVC at 7 days. After laser Doppler imaging, DVT were separated and weighed, and vein wall stiffness was assessed by tensiometry. Thrombus and vein wall tissue analysis included total collagen by colorimetric assay, cytokines, chemokines, and D-dimer by ELISA, urokinase-plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1) by immuno-blotting, NMP-2 and -9 by zymography, and neutrophil (PMN) and monocyte (ED-1) leukocytes by immunohistochemistry.Results. DVT weights were 2-fold greater in the AP-treated rats (P < 0.05), but no significant differences in thrombus perfusion, collagen, or D-dimer levels were found. Vein wall stiffness was reduced 50% (P < 0.05), suggesting less biomechanical injury. The total vein wall MMP-9 was increased (P < 0.05) 5-fold in the AP group compared with controls, while MMP-2 was elevated but did not reach significance. No difference was found in vein wall tumor necrosis factor-alpha, tissue growth factor-beta, vein wall or thrombus monocytes, PMN, or uPA/PAI-1 ratio between groups.Discussion. AP inhibition of the plasmin system was associated with larger thrombi but less vein wall injury, but no difference in other measures of resolution, possibly because of increased vein wall MMP-9 activity. These data suggest an important redundant mechanism for DVT resolution. (C) 2007 Elsevier Inc. All rights reserved.