Treatment with an oral small molecule inhibitor of P selectin (PSI-697) decreases vein wall injury in a rat stenosis model of venous thrombosis
Treatment with an oral small molecule inhibitor of P selectin (PSI-697) decreases vein wall injury in a rat stenosis model of venous thrombosis
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DOI：
10.1016/j.jvs.2006.05.021
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发表时间：
2006-09-01
影响因子：
4.3
通讯作者：
Wakefield, Thomas W.
中科院分区：
文献类型：
--
作者：
Myers, Daniel D., Jr.;Henke, Peter K.;Wakefield, Thomas W.
背景：血栓形成后的静脉壁损伤是多因素的，但似乎依赖于血栓和局部血栓形成和炎症机制。我们假设，在大鼠静脉血栓模型中，p选择素抑制和/或低分子肝素（LMWH）通过减少血栓和炎症事件来抑制静脉壁损伤，而不依赖于血栓的溶解。方法：雄性大鼠下腔静脉（IVC）狭窄（94.4% +/- 0.5%）。下腔静脉直径)诱发血栓形成。大鼠从血栓形成后第2天开始治疗，直到第7天处死。各组包括(1)p选择素抑制剂PSI-697 （30 mg/kg，每日口服）；(2) LMWH-Lovenox （LOV；依诺肝素）每日皮下注射3mg /kg；(3) PSI-697 （30 mg/kg，每日灌胃）加LOV 3 mg/kg，每日皮下注射（PSI + LOV）；(4)和未经处理的对照。评估包括血栓块、静脉壁张力测量（僵硬度[顺应性相反]）、光镜下的内膜厚度评分、酶联免疫吸附法检测的静脉壁炎症介质和组织学评估的静脉壁炎症细胞。结果：任何治疗均未减少血栓块。与对照组相比，单独使用PSI-697、单独使用LOV或PSI + LOV治疗的动物显示静脉壁刚度显著降低。psi -697治疗组的静脉壁刚度也明显低于单纯lov治疗组。与对照IVCs相比，PSI-697治疗的动物内膜厚度评分显著降低。与LOV相比，PSI-697治疗的动物的静脉壁内膜增厚也显著减少。PSI-697和PSI + LOV组与对照组和LOV组相比，免疫调节和炎症细胞因子白细胞介素13显著降低。与对照组相比，PSI-697和PSI + LOV组的静脉壁单核细胞趋化蛋白1水平也显著降低。只有PSI-697显著降低静脉壁血小板衍生生长因子β β的水平。与对照组相比，LOV组和PSI + LOV组的静脉壁单核细胞和总炎症细胞均显著增加。结论：这些数据表明低分子肝素和PSI-697对静脉壁损伤的抑制独立于血栓块。p -选择素的抑制似乎优于低分子肝素在损伤和介质抑制的测量参数。
Background: Vein wall injury after thrombosis is multifactorial but seems dependent on thrombus and local thrombotic and inflammatory mechanisms. We hypothesized that inhibition of vein wall injury through reduction of thrombotic And inflammatory events with P-selectin inhibition and/or low-molecular-weight heparin (LMWH) occurs independently of thrombus resolution in a rat model of venous thrombosis.Methods: Male rats underwent inferior vena cava (IVC) stenosis (94.4% +/- 0.5% reduction in. IVC diameter) to induce thrombosis. Rats were treated from 2 days after thrombosis until they were killed 7 days later. Groups consisted of (1) PSI-697, a P-selectin inhibitor (30 mg/kg; oral gavage daily); (2) LMWH-Lovenox (LOV; enoxaparin) 3 mg/kg subcutaneously daily; (3) PSI-697 (30 mg/kg; oral gavage daily) plus LOV 3 mg/kg subcutaneously daily (PSI + LOV); (4) and untreated controls. Evaluations included thrombus mass, vein wall tensiometry (stiffness [inverse of compliance]), intimal thickness scoring by light microscopy, vein wall inflammatory mediators by enzyme-linked immunosorbent assay, and vein wall inflammatory cells by histologic evaluation.Results: Thrombus mass was not reduced by any treatment. Animals treated with PSI-697 alone, LOV alone, or PSI + LOV demonstrated significant decreases in vein wall stiffness when compared with controls. The vein wall stiffness of the PSI-697-treated groups was also significantly lower than in the LOV-only group. Animals treated with PSI-697 showed a significantly decreased intimal thickness score when compared with vehicle control IVCs. Vein wall intimal thickening was also significantly decreased in animals treated with PSI-697 vs LOV. The PSI-697 and PSI + LOV groups manifested significant decreases in the immunoregulatory and inflammatory cytokine interleukin 13 as compared with controls and LOV. Vein wall monocyte chemotactic protein 1 levels were also significantly reduced in the PSI-697 and PSI + LOV groups vs control. Only PSI-697 significantly decreased vein wall levels of platelet-derived growth factor beta beta. Both the LOV and PSI + LOV groups had significant increases in vein wall monocytes and total inflammatory cells vs controls.Conclusions: These data suggest that both LMWH and PSI-697 inhibit vein wall injury independently of thrombus mass. P-selectin inhibition seemed superior to LMWH in measured parameters of injury and mediator inhibition.