The Role of IL-6 in Experimental Post Thrombotic Syndrome

IL-6 在实验性血栓后综合症中的作用

• 批准号: 9279245
• 负责人: PETER K HENKE
• 金额: $ 47.19万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9279245
• 关键词: Address; Antibodies; Anticoagulation; Apoptosis; Apoptotic; Binding; Blood Platelets; Blood Vessels; Bone Marrow; Cell Count; Cells; Chimera organism; Clinical; Complex; Compression Stocking; Data; Deep Vein Thrombosis; Disease; Disintegrins; Endothelial Cells; Failure; Fibrosis; Functional disorder; Hemorrhage; Hepatocyte; IL6ST gene; Inflammatory; Injury; Interleukin-6; Knowledge; Lead; Leukocytes; Low-Molecular-Weight Heparin; Mediating; Medical; Membrane; Metalloproteases; Mission; Modeling; Morbidity - disease rate; Mus; Muscle Cells; Organ Culture Techniques; Patients; Postphlebitic Syndrome; Public Health; Publishing; Recurrence; Research; Risk; Role; Signal Pathway; Signal Transduction; Source; Stenosis; System; Testing; Thrombosis; Thrombus; Tissues; Transgenic Mice; Translations; United States National Institutes of Health; Vascular Smooth Muscle; Veins; Venous Thrombosis; clinical translation; cytokine; design; experimental study; in vivo; interleukin-6 receptor alpha; mortality; mouse model; neutrophil; novel; prevent; receptor; response; standard of care; thrombolysis; treatment strategy

ABSTRACT Post-thrombotic syndrome (PTS) is the most common sequelae from deep vein thrombosis (DVT), characterized by vein wall fibrosis, valve destruction and often occlusion. It is estimated to occur in ~40 – 50% of those suffering a DVT. No direct medical therapy exists to treat PTS, highlighted by the recent failure of graded compression stockings to prevent PTS (SOX trial). The CaVenT trial suggested that even those patients treated with thrombolysis still have a ~40% incident PTS at 2 years. Recurrent DVT is a particularly strong factor increasing the risk of PTS, prevented in part by anticoagulation. However, bleeding risks remain even with the new non-vitamin-K antagonists. Interleukin-6 (IL-6) is a pleotropic inflammatory cytokine that is uniquely associated with both PTS and experimental vein wall injury. IL-6 has two primary signaling pathways. Direct IL-6 binding to membrane bound IL-6 receptor-alpha (Rα) occurs in a limited number of cells, such as hepatocytes and leukocytes, and is termed `classical'. More commonly, IL-6 complexes with soluble IL-6Rα and binds the co-receptor gp130, present on most cells, termed `trans-signaling', and confers most inflammatory and fibrotic sequelae. Preliminary and published data suggests strong correlation of IL-6 with vein wall fibrosis, co-localization with endothelial and vascular smooth muscle cells (VSMC), and altered fibrosis in IL-6-/- mice after venous thrombosis (VT). These observations suggest a central role for IL-6 signaling in post- thrombotic vein wall injury, and importantly, for which readily translatable anti-IL-6 therapies already exist. Our overall hypothesis is that IL-6/sIL-6R trans-signaling drives downstream profibrotic vein wall cellular changes that cause experimental post-thrombotic vein wall injury and that novel anti-IL-6 signaling therapies can abrogate post-thrombotic vein wall injury. We will address this hypothesis by three specific aims: Specific Aim 1: To define the early sources and mechanisms of IL-6 and sIL-6R release after VT, the early vein wall cellular responses, and the effect of thrombosis model. Specific Aim 2: To demonstrate the vein wall endothelial and VSMC specific profibrotic activities driven by IL-6/IL-6R/gp130 signaling axis after VT. Specific Aim 3: To prevent and treat post-thrombotic vein wall injury using novel direct and indirect anti-IL-6 therapies, as a comparison with standard of care anticoagulation, in primary and recurrent experimental VT. To accomplish these Aims, murine models of stasis and stenosis derived VT, as well as ex vivo vein wall culture will be used. Tissue specific transgenic mice to define the mechanisms of IL-6 signaling on vein wall fibrotic injury, and novel non anticoagulant anti-IL-6 therapies will be tested. The proposed experiments herein will significantly move the field forward by defining the mechanisms of IL-6 signaling, and the translation of IL-6 inhibition on experimental PTS, using novel and clinically available agents.

摘要 血栓后综合征（PTS）是深静脉血栓形成（DVT）最常见的后遗症， 其特征在于静脉壁纤维化、瓣膜破坏和经常闭塞。估计发生率约为40 - 50% 那些患有DVT的人。没有直接的药物治疗存在治疗PTS，突出表现为最近的失败， 分级压缩长袜，以防止PTS（SOX试验）。CaVentt试验表明，即使是那些 接受溶栓治疗的患者在2年时仍有约40%的PTS事件。复发性DVT是一种特别 增加PTS风险的强因素，部分通过抗凝治疗预防。然而，出血风险仍然存在 即使是新的非维生素K拮抗剂白细胞介素-6（IL-6）是一种多效性炎性细胞因子， 与PTS和实验性静脉壁损伤唯一相关。IL-6有两条主要的信号通路。 IL-6与膜结合的IL-6受体-α（Rα）的直接结合发生在有限数量的细胞中，例如 肝细胞和白细胞，并被称为“经典”。更常见的是，IL-6与可溶性IL-6 R α复合， 并结合存在于大多数细胞上的共受体gp 130，称为“反式信号传导”， 炎症和纤维化后遗症。初步和已发表的数据表明，IL-6与静脉 血管壁纤维化，与内皮细胞和血管平滑肌细胞（VSMC）共定位， 静脉血栓形成（VT）后的IL-6-/-小鼠。这些观察结果表明，IL-6信号转导在肿瘤后生长中的核心作用。 血栓性静脉壁损伤，并且重要的是，对于其已经存在容易转化的抗IL-6疗法。我们 总的假设是IL-6/sIL-6 R β反式信号转导驱动下游促纤维化静脉壁细胞变化 其引起实验性血栓形成后静脉壁损伤，并且新的抗IL-6信号传导疗法可以 消除血栓形成后静脉壁损伤。我们将通过三个具体目标来解决这个假设： 1：明确VT后IL-6和sIL-6 R β释放的早期来源和机制， 细胞反应和血栓形成模型的影响。具体目标2：显示静脉壁 VT后由IL-6/IL-6 R β/gp 130信号轴驱动的内皮和VSMC特异性促纤维化活性。 具体目标3：使用新型直接和间接抗IL-6预防和治疗血栓后静脉壁损伤 在原发性和复发性实验室性室性心动过速中，与标准抗凝治疗进行比较。 为了实现这些目的，在小鼠模型中建立了淤滞和狭窄衍生的VT，以及离体静脉壁， 文化将被使用。组织特异性转基因小鼠静脉壁IL-6信号转导机制的研究 纤维化损伤和新的非抗凝抗IL-6疗法。本文提出的实验 将通过定义IL-6信号传导机制和IL-6的翻译， 抑制实验PTS，使用新的和临床上可用的代理。