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: 7278135
• 负责人: PETER K HENKE
• 金额: $ 35.45万
• 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/7278135
• 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

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.

描述（申请人提供）： 本申请的广泛、长期目标是更好地定义深静脉血栓形成（DVT）后静脉壁重塑的机制，着眼于改变发生的损伤，并允许转化为人类治疗。下肢深静脉血栓形成后出现的并发症有相当一部分患者会导致腿部疼痛、肿胀，偶尔也会出现溃疡。就生产力损失和需要重复的医疗保健访问而言，社会的成本是巨大的。虽然存在有效的治疗方法来防止DVT传播，但不存在直接改变静脉壁损伤的方法。DVT后静脉壁重塑的基本机制包括炎性细胞内流、促纤维化生长因子的产生、胶原和弹性蛋白的更新以及基质金属蛋白酶（MMP）的激活。具体而言，初步数据强烈表明，静脉壁的反应不同，这取决于血栓接触的性质和持续时间，并与MMP-2和-9活性增加有关。这些蛋白酶是否是早期损伤和后期纤维化的原因尚不清楚，也不可能预测哪些患者可能发展为纤维化后综合征。目前超声和外周血白细胞MMPs在急性和慢性DVT中的基因表达是一个未研究的领域。总的假设是，淤滞性血栓形成通过mmp激活引起静脉壁损伤，导致晚期纤维化损伤。目前的研究将通过以下具体目的利用DVT的体内啮齿动物模型和一系列患有DVT的人类患者来评估该假设：在DVT大鼠模型中研究：A）血栓形成条件调节静脉壁MMP-2、MMP-9表达的机制;和B）确定外源性MMP抑制剂是否可以减轻早期静脉壁损伤; II.证明MMP-2和MMP-9活性的下调抑制小鼠模型中停滞性DVT后的晚期静脉壁纤维化损伤; III.目的通过多普勒超声检查和外周血白细胞基因和血清蛋白MMP-2和-9表达来确定人类DVT后持续的静脉壁损伤。这一建议将提供重要的机制洞察到发病后综合征的病理生理学与真实的潜在的翻译，以减少发病率从这种欠承认的疾病。