Vein wall remodeling after DVT is matrix metalloproteinase dependent

描述(由申请人提供)： 这项应用的广泛、长期目标是更好地确定深静脉血栓形成(DVT)后静脉壁重塑的机制，着眼于改善所发生的损害，并允许将其转化为人类治疗。静脉炎后综合征在相当数量的患者DVT后发生，并导致腿部疼痛、肿胀，偶尔还会出现溃疡。就生产力损失和需要反复就医而言，这给社会带来了巨大的代价。虽然有有效的治疗方法可以防止DVT的传播，但没有一种方法可以直接改善静脉壁的损害。DVT后静脉壁重塑的基本机制包括炎症细胞内流、促纤维化生长因子的产生、胶原和弹性蛋白的周转以及基质金属蛋白酶(MMPs)的激活。具体地说，初步数据强烈表明，根据血栓接触的性质和持续时间，静脉壁的反应不同，并与增加的基质金属蛋白酶-2和-9活性有关。目前尚不清楚这些蛋白水解酶是否导致早期损伤和后来的纤维化，也不可能预测哪些患者可能发展为静脉炎后综合征。目前超声检查和外周血白细胞基因表达MMPs在急慢性DVT中的表达尚无研究。总体的假说是，血栓形成通过激活基质金属蛋白酶导致静脉壁损伤，导致晚期纤维化损伤。本研究将利用DVT的活体啮齿动物模型和一系列患有DVT的人类患者对这一假说进行评估，具体目的如下：1)在DVT大鼠模型中探讨血栓条件调节静脉壁MMP2、-9表达的机制；B)确定外源性MMP2、9抑制剂是否能减轻早期静脉壁损伤；II.证明在DVT停滞后，MMP2和MMP9活性下调可抑制晚期静脉壁纤维化损伤；应用双功能超声检测DVT后人类静脉壁的持续损伤情况，以及外周血白细胞基因和血清蛋白MMP2、9的表达情况。这一建议将提供重要的机制洞察后静脉曲张综合征的病理生理学与真正的潜在转化，以减少这种被低估的疾病的发病率。

Description (provided by Applicant): 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.