Vein wall remodeling after DVT is matrix metalloproteinase dependent

DVT 后静脉壁重塑依赖于基质金属蛋白酶

• 批准号: 7392799
• 负责人: PETER K HENKE
• 金额: $ 36.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392799
• 关键词: Acute; Anticoagulant therapy; Apoptosis; Area; Attenuated; Blood Coagulation Factor; Cell Proliferation; Cells; Chronic; Cicatrix; Collagen; Condition; Data; Deep Vein Thrombosis; Development; Disease; Down-Regulation; Elastin; Endopeptidases; Environment; Equilibrium; Extracellular Matrix Proteins; Eye; Fatigue; Fibrosis; Functional disorder; Genes; Genetic; Goals; Growth Factor; Health Care Visit; Human; Inflammatory; Injury; Leukocytes; Limb structure; Matrix Metalloproteinases; Mediating; Modeling; Morbidity - disease rate; Nature; Numbers; Pain; Pain in lower limb; Patients; Peptide Hydrolases; Peripheral; Postphlebitic Syndrome; Production; Productivity; Prophylactic treatment; Rattus; Reaction; Research Personnel; Resolution; Rodent Model; Series; Serum Proteins; Societies; Stretching; Swelling; Symptoms; Syndrome; Thrombosis; Thrombus; Tissues; Translations; Ulcer; Ultrasonography; Veins; Venous; cost; ilium; in vivo; inhibitor/antagonist; insight; mouse model; neglect; prevent; programs; response; thrombolysis

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.

该应用程序的广泛、长期目标是更好地定义深静脉后的机制 血栓形成 (DVT) 静脉壁重塑着眼于改变发生的损伤，并允许 转化为人类疗法。相当多的患者在 DVT 后出现静脉炎后综合征 并导致腿部疼痛、肿胀，偶尔还会出现溃疡。就损失而言，社会成本是巨大的 生产力，以及重复医疗保健就诊的需要。虽然存在预防 DVT 的有效疗法 传播，不存在直接改变静脉壁损伤的方法。静脉壁的基本机制 DVT 后的重塑包括炎症细胞流入、促纤维化生长因子产生、胶原蛋白和 弹性蛋白周转和基质金属蛋白酶 (MMP) 激活。具体来说，初步数据强烈 表明静脉壁根据血栓接触的性质和持续时间做出不同的反应 且与 MMP-2 和 -9 活性增加有关。这些蛋白酶是否负责 早期损伤和后期纤维化尚不清楚，也无法预测哪些患者可能会在术后发生 静脉综合症。目前可用的超声检查和外周血白细胞基因表达 MMP 在急性和慢性 DVT 中的作用是一个尚未研究的领域。 总体假设是 MMP 导致瘀血性血栓形成静脉壁损伤 激活，导致晚期纤维化损伤。目前的研究将评估这一假设 利用 DVT 的体内啮齿动物模型和一系列患有 DVT 的人类患者，具体方法如下 目的： I. 在 DVT 大鼠模型中研究：A) 血栓条件调节静脉的机制 壁MMP-2、-9表达； B) 确定外源性 MMP 抑制剂是否可以减弱早期静脉壁 受伤;二.证明下调 MMP-2 和 -9 活性可抑制晚期静脉壁纤维化损伤 小鼠模型中发生停滞性 DVT 后；三．定义人类 DVT 后持续的静脉壁损伤 双功能超声检查以及外周血白细胞基因和血清蛋白MMP-2和-9的表达。 该提案将为后静脉炎综合征的病理生理学提供重要的机制见解 具有降低这种未被充分认识的疾病的发病率的真正潜力。