Vein wall remodeling after DVT is matrix metalloproteinase dependent

这项应用的广泛、长期目标是更好地定义后深静脉的机制 血栓形成(DVT)静脉壁重塑，着眼于修改发生的损害，并允许 转化为人类疗法。静脉曲张后综合征在相当数量的患者中发生在DVT后 导致腿部疼痛、肿胀，偶尔还会出现溃疡。从损失的角度来看，社会的代价是巨大的 生产力，以及需要重复的医疗保健访问。虽然有有效的治疗方法来预防DVT 传播，不存在直接修改脉壁损伤的方法。静脉壁的基本机制 DVT后的重塑包括炎性细胞内流、促纤维化生长因子的产生、胶原和 弹性蛋白周转和基质金属蛋白酶(MMPs)激活。具体地说，初步数据强劲 提示根据血栓接触的性质和持续时间，静脉壁的反应是不同的。 并与基质金属蛋白酶-2和-9的活性增加有关。这些蛋白水解酶是否对 早期损伤和后来的纤维化尚不清楚，也不可能预测哪些患者可能在术后发生 静脉炎综合征。目前可用的超声检查和外周血白细胞基因表达 MMPs在急慢性DVT中的作用是一个未被研究的领域。 总的假说是血瘀性血栓形成通过基质金属蛋白酶引起静脉壁损伤 活化，导致晚期纤维化损伤。目前的研究将对这一假设进行评估 利用DVT的活体啮齿动物模型和一系列患有DVT的人类患者通过以下特定的方法 目的：1.探讨大鼠深静脉血栓形成模型：a)血栓状态调节静脉的机制 壁基质金属蛋白酶-2、-9的表达；以及B)确定外源性基质金属蛋白酶抑制剂是否可以减弱早期静脉壁 2.证明基质金属蛋白酶-2和-9活性下调抑制晚期静脉壁纤维化损伤 在小鼠模型中的DVT停滞后；III.通过以下方法确定DVT后人类持续的静脉壁损伤 双功超声检查，外周血白细胞基因和血清蛋白表达。 这一建议将为了解静脉炎后综合征的病理生理学提供重要的机械学见解。 具有真正的潜力，以减少这种被低估的疾病的发病率。

This application's broad, long term objectives are to better define the mechanisms of post deep vein thrombosis (DVT) vein wall remodeling with an eye towards modifying the damage that occurs, and allow translation to human therapy. Post phelbitic syndrome occurs after DVT in a significant number of patients and results in leg pain, swelling, and occasionally ulceration. The costs to society are great in terms of lost productivity, and need for repeated health care visits. While efficacious therapy exists to prevent DVT propagation, none exist that directly modify vein wall damage. The basic mechanisms of vein wall remodeling after DVT include inflammatory cell influx, profibrotic growth factor production, collagen and elastin turnover, and matrixmetalloproteinases (MMP) activation. Specifically, preliminary data strongly suggests that the vein wall responds differently depending on the nature and duration of thrombus contact and is associated with increased MMP-2 and -9 activity. Whether these proteinases are responsible for the early damage and later fibrosis is not known, nor is it possible to predict which patients may develop post- phelbitic syndrome. Currenly available ultrasonographic and peripheral leukocyte genetic expression of MMPs in the setting of acute and chronic DVT is an unstudied area. THE OVERALL HYPOTHESIS IS THAT STASIS THROMBOSIS CAUSES VEIN WALL DAMAGE BY MMP ACTIVATION, LEADING TO LATE FIBROTIC INJURY. The current study will evaluate this hypothesis utilizing in vivo rodent models of DVT and a series of human patients with DVT by the following Specific Aims: I. To investigate in rat model of DVT: A) The mechanism by which thrombotic conditions regulate vein wall MMP-2, -9 expression; and B) To determine if exogenous MMP inhibitors can attenuate early vein wall injury; II. To demonstrate that down-regulation of MMP-2 and -9 activity inhibits late vein wall fibrotic injury after stasis DVT in a mouse model; III. To define ongoing vein wall injury in humans following DVT by duplex ultrasonography, and peripheral leukocyte gene and serum protein MMP-2 and -9 expression. This proposal will provide important mechanistic insight into the pathophysiology of post-phelbitic syndrome with real potential translation to decreasing the morbidity from this under-acknowledged disease.