Fibrotic injury after experimental deep vein thrombosis is determined by the mechanism of thrombogenesis
Fibrotic injury after experimental deep vein thrombosis is determined by the mechanism of thrombogenesis
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DOI：
10.1160/th07-03-0190
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发表时间：
2007-11-01
影响因子：
6.7
通讯作者：
Wakefield, Thomas W.
中科院分区：
文献类型：
--
作者：
Henke, Peter K.;Varma, Manu R.;Wakefield, Thomas W.
血管壁基质的变化发生损伤后，虽然这还没有得到很好的研究，在静脉系统。本研究检验了血栓决定静脉壁反应和静脉壁损伤与血栓接触持续时间直接相关的假设。为了确定随时间的损伤反应，对大鼠进行下腔静脉（IVC）结扎以产生淤滞血栓，在不同时间点至28天（d）收获。生物力学损伤后静脉壁基质发生明显变化（僵硬）在7-14天达到峰值，同时伴有总胶原的早期减少，早期基质金属蛋白酶（MMP）-9和晚期MMP-2的增加，以及肿瘤坏死因子（TNF）α的伴随增加，单核细胞趋化因子（MCP）-I和肿瘤生长因子（TGF）β为探讨血栓形成的作用及其机制，分别对大鼠进行7 d或限制性血栓形成实验（24小时）、非淤滞性血栓形成或非血栓性IVC闭塞（硅胶塞）。与对照组相比，静脉壁硬度增加7倍，胶原蛋白减少5倍，TNF α、MCP-1和TGF β增加5.5至7倍（均P < 0.05）。通过Picosirus红染色分析，胶原溶解在7 d的瘀滞损伤中显著更大（P = 0.01），但MMP-9和MMP-2活性与损伤机制均不相关。静脉壁细胞增殖和uPA基因表达与血栓性损伤并行。有限淤滞、非淤滞血栓形成和非血栓性IVC闭塞显示出较低的炎症反应。这些数据表明，静态成分和血栓通过多种机制引导静脉壁损伤。
Vessel wall matrix changes occur after injury, although this has not been well studied in the venous system. This study tested the hypothesis that the thrombus dictates the vein wall response and vein wall damage is directly related to the duration of thrombus contact. To determine the injury response over time, rats underwent inferior vena cava (IVC) ligation to produce a stasis thrombus, with harvest at various time points to 28 days (d). Significant vein wall matrix changes occurred with biomechanical injury (stiffness) peaking at 7-14 d, with concurrent early reduction in total collagen, an increase in early matrix metalloproteinase (MMP)-9 and late MMP-2, and concomitant increase in tumor necrosis factor (TNF)alpha, monocyte chemoattractant(MCP)-I and tumor growth factor (TGF)beta (all P < 0.05).To isolate the effect of the thrombus and its mechanism of genesis, rats underwent 7 d or limited stasis (24 hours), non-stasis thrombosis, or non-thrombotic IVC occlusion (Silicone plug). Vein wall stiffness was increased seven-fold, with a five-fold reduction in collagen, and 5.5- to seven-fold increase in TNF(X, MCP-I, and TGF beta with 7 d stasis as compared with controls (all P < 0.05). By Picosirus red staining analysis, collagenolysis was significantly greater with 7 d stasis injury (P = 0.01) but neither MMP-9 nor MMP-2 activity correlated with injury mechanism. In addition,vein wall cellular proliferation and uPA gene expression paralled the stasis thrombotic injury. Limited stasis, non-stasis thrombosis and non-thrombotic IVC occlusion showed a lesser inflammatory response. These data suggest both a static component and the thrombus directs vein wall injury via multiple mechanisms.