Vein wall remodeling after deep vein thrombosis: differential effects of low molecular weight heparin and doxycycline.
Vein wall remodeling after deep vein thrombosis: differential effects of low molecular weight heparin and doxycycline.
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DOI：
10.1016/j.avsg.2009.11.002
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发表时间：
2010-02
影响因子：
1.5
通讯作者：
Henke, Peter K.
中科院分区：
文献类型：
--
作者：
Sood, Vikram;Luke, Cathy;Miller, Erin;Mitsuya, Mayo;Upchurch, Gilbert R., Jr.;Wakefield, Thomas W.;Myers, Dan D.;Henke, Peter K.
静脉血栓消退会引起早期强烈的炎症反应，从而导致静脉壁损伤。组织对损伤的反应包括基质金属蛋白酶（MMP）激活和细胞外基质蛋白周转。本研究旨在确定外源性MMP抑制的效果及其对早期静脉壁损伤的潜在衰减。大鼠通过近闭塞性结扎在停滞静脉血栓形成后24小时开始接受治疗，直到第7天收获。评估了三组：1）。载体盐水对照（NaCl）; 2）. LMWH（Lovenox，3 mg/Kg/天SQ）; 3）。多西环素（DOXY; 30 mg/Kg/天PO）。评估血栓大小（mg/mm）、比色法测定的TNFα和d-二聚体水平以及免疫组织化学法测定的艾德-1计数。静脉壁评估包括张力测量法测量的硬度、ELISA法测量的ILβ蛋白水平、酶谱法测量的MMP 2和-9以及内膜厚度（IT）的组织学分析。通过t检验与对照进行比较。P <0.05被认为是显著的。所有三组在第2天和第7天的血栓大小相似，而第2天LMWH和DOXY治疗组的血栓TNFα升高（NaCl = 1.0± 0.8，LWMH = 9 ±3*，DOXY = 27±5*，pg/mg蛋白，N = 6 - 8，P <0.05）; DOXY组7 d时（NaCl = 3.0±2.5，DOXY = 23±4.2*，pg/mg蛋白，N = 5，P <0.05）。与对照组相比，LMWH处理组静脉壁硬度在第7天较低，但DOXY处理组无此差异（NaCl = .33±.05，LMWH =.17±.03*，DOXY = .43±.09 N/mm，N = 5-7，P < .05）。在第7天，仅DOXY组的血管壁IL-1β降低（NaCl = 26±3，LMWH = 38±17，DOXY = 6±3* pg/mg蛋白，N = 4 - 6，P <0.05），与对照组相比，IT评分也是如此（NaCl = 2.2± 0.6，LMWH =1.7± 0.3，DOXY = 0.8 ± 0.20 *，IT评分，N = 4 - 6，P <0.05）。在LMWH和DOXY组中，酶谱MMP 9活性在第2天显著降低（NaCl = 85±24，LMWH = 23±7*，DOXY = 13±5* U/mg蛋白，N = 6 - 8，P <0.05）。MMP 2酶谱活性、血栓单核细胞计数和d-二聚体活性在各组间无显著差异。LMWH或DOXY治疗并没有改变DVT的大小，轻微改变血栓成分，以及不同程度影响静脉壁损伤，尽管早期MMP 9活性降低相似。外源性MMP抑制是否影响长期静脉壁纤维化还需要进一步研究。
Venous thrombus resolution sets up an early intense inflammatory reaction, from which vein wall damage results. Tissue response to injury includes matrix metalloproteinase (MMP) activation and extracellular matrix protein turnover. This study sought to determine the effect of exogenous MMP inhibition and its potential attenuation of early vein wall injury. Rats received treatment beginning 24 hours after a stasis venous thrombosis by near occlusive ligation, and until harvest at day 7. Three groups were evaluated: 1). Vehicle saline controls (NaCl); 2). LMWH (Lovenox, 3 mg/Kg per day SQ); 3). Doxycycline (DOXY; 30 mg/Kg per day PO). Thrombus size (mg/mm), levels of TNFα and d-Dimer by colorimetric assay, and ED-1 counts by immunohistochemistry were assessed. Vein wall assessment included stiffness by tensiometry, ILβ protein levels by ELISA, MMP2 and -9 by zymography, and histological analysis of intimal thickness (IT). Comparisons were by t-Test to control. A P < .05 was considered significant. Thrombi sizes were similar at both days 2 and 7 for all three groups, while thrombus TNFα was increased in 2d LMWH and DOXY treated groups (NaCl = 1.0±.8, LWMH = 9 ±3*, DOXY = 27±5*, pg/mg protein, N = 6 - 8, P < .05); and at 7d in the DOXY group (NaCl = 3.0±2.5, DOXY = 23±4.2*, pg/mg protein, N = 5, P < .05). Vein wall stiffness was less with LMWH treatment at 7d, but not with DOXY, as compared with controls (NaCl = .33±.05, LMWH =.17±.03*, DOXY = .43±.09 N/mm, N = 5-7, P < .05). Vessel-wall IL-1β was reduced only in the DOXY group at 7d (NaCl = 26±3, LMWH = 38±17, DOXY = 6±3* pg/mg protein, N = 4 - 6, P < .05) as was the IT score versus controls (NaCl = 2.2±.6, LMWH =1.7±.3, DOXY = 0.8 ± .20*, IT score, N = 4 -6, P < .05). Zymographic MMP9 activity was significantly reduced at 2 days in the LMWH and DOXY groups (NaCl = 85±24, LMWH = 23±7*, DOXY = 13±5* U/mg protein, N = 6 - 8, P < .05). MMP2 zymographic activity, thrombi monocyte cell counts, and d-Dimer activity were not significantly different across groups. Treatment with LMWH or DOXY did not alter size of DVT, mildly altered thrombus composition, and differentially affected vein wall injury, despite similar reductions in early MMP9 activity. Whether exogenous MMP inhibition affects long-term vein wall fibrosis will require further study.
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影响因子：
2.2
作者：
Dewyer, Nicholas A.;Sood, Vikram;Henke, Peter K.
通讯作者：
Henke, Peter K.
影响因子：
4.3
作者：
Myers, Daniel D., Jr.;Henke, Peter K.;Wakefield, Thomas W.
通讯作者：
Wakefield, Thomas W.
影响因子：
4.3
作者：
Meissner, MH;Caps, MT;Strandness, DE
通讯作者：
Strandness, DE
影响因子：
19.6
作者：
Hogaboam, CM;Steinhauser, ML;Kunkel, SL
通讯作者：
Kunkel, SL
影响因子：
37.8
作者：
Gennaro, G;Ménard, C;Rivard, A
通讯作者：
Rivard, A