Cytokine Driven Mechanisms of Vein Graft Failure

静脉移植失败的细胞因子驱动机制

• 批准号: 7076231
• 负责人: C KEITH OZAKI
• 金额: $ 31.97万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076231
• 关键词: biological signal transduction; cell proliferation; cytokine receptors; gene expression; genetically modified animals; graft versus host disease; heart /lung bypass; hemodynamics; hyperplasia; inflammation; interleukin 10; laboratory mouse; laboratory rabbit; postoperative complications; shear stress; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Surgical vein bypass grafts fail principally due to development of neointimal hyperplasia, especially in the setting of low flow within the conduit. Inflammation stands as a pathologic feature of this process. While cytokines have been implicated in vein graft failure, the initiating factors and signaling mechanisms for their expression (as well as the biologic implications of these inflammatory mediators in vein wall adaptations) remain largely unknown. Prior studies by our group directly implicate the production of both the proinflammatory cytokine TNF-alpha and anti-inflammatory cytokine IL-10 in modulation of arterial wall adaptations to changes in wall shear. In recent work we demonstrated specific time and flow dependent cytokine signatures in the early arterialized vein graft. TNF-alpha expression is induced almost 200-fold within 24 hours in low flow grafts that subsequently develop robust intimal hyperplasia, while high flow promotes a delayed induction of IL-10 mRNA expression, which appears to protect against occlusive adaptations. This proposal moves forward by testing two linked mechanistic hypotheses: 1) Vein grafts develop neointimal hyperplasia by way of low wall shear induced pro-inflammatory cytokine driven mechanisms (soluble TNF-alpha signaling via the p55 receptor, leading to enhanced leukocyte mediated inflammation, and increased cell proliferation). Signaling pathways will be dissected by studying vein grafts in mice lacking soluble TNF-alpha or the p55 or p75 receptor. Under differential flow environments, TNF-alpha signaling will be defined through inhibition by soluble receptors, adeno-associated virus (AAV)-delivered TNF receptor homologs, specific p55 or p75 TNF receptor antibodies, or TNF-alpha converting enzyme inhibition. 2) IL-10 production protects vein grafts from over exuberant occlusive wall adaptations via reduced inflammatory leukocyte infiltration, myofibroblast proliferation, and down-regulation of TNF-alpha production. Vein grafts from IL-10 knockout mice will be examined, as well as conduits after treatment with exogenous IL-10 (both pharmacologic and AAV vIL-10). Based on new knowledge and skills obtained during the applicant's research training, the fundamental design of this initial independent proposal is to transfer basic cytokine biology to vascular biology, and through new mechanistic insights, translate these findings into strateqies to improve vein (draft durability).

描述（由申请人提供）： 外科静脉旁路移植术失败的主要原因是新内膜增生，特别是在导管内流量低的情况下。炎症是这一过程的病理特征。虽然细胞因子与静脉移植失败有关，但其表达的起始因素和信号传导机制（以及这些炎症介质在静脉壁适应中的生物学意义）仍然很大程度上未知。我们小组之前的研究直接表明促炎细胞因子 TNF-α 和抗炎细胞因子 IL-10 的产生与动脉壁适应壁剪切力变化的调节有关。在最近的工作中，我们证明了早期动脉化静脉移植物中特定的时间和流量依赖性细胞因子特征。在低流量移植物中，TNF-α 表达在 24 小时内被诱导近 200 倍，随后形成强大的内膜增生，而高流量则促进 IL-10 mRNA 表达的延迟诱导，这似乎可以防止闭塞适应。该提议通过测试两个相关的机制假设来推进：1）静脉移植物通过低壁剪切诱导的促炎细胞因子驱动机制（通过 p55 受体的可溶性 TNF-α 信号传导，导致白细胞介导的炎症增强，并增加细胞增殖）发展新内膜增生。将通过研究缺乏可溶性 TNF-α 或 p55 或 p75 受体的小鼠的静脉移植物来剖析信号通路。在不同的流动环境下，TNF-α 信号传导将通过可溶性受体的抑制、腺相关病毒 (AAV) 传递的 TNF 受体同源物、特定的 p55 或 p75 TNF 受体抗体或 TNF-α 转换酶抑制来定义。 2) IL-10 的产生通过减少炎症白细胞浸润、肌成纤维细胞增殖和 TNF-α 产生的下调来保护静脉移植物免受过度旺盛的闭塞壁适应。将检查来自 IL-10 敲除小鼠的静脉移植物，以及用外源性 IL-10（药理学和 AAV vIL-10）处理后的导管。 基于申请人在研究培训中获得的新知识和技能，这个最初的独立提案的基本设计是将基本的细胞因子生物学转移到血管生物学，并通过新的机制见解，将这些发现转化为改善静脉（草案耐久性）的策略。