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: 6860622
• 负责人: C KEITH OZAKI
• 金额: $ 32.74万
• 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/6860622
• 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）： 外科静脉旁路移植失败主要是由于新生内膜增生的发展，特别是在管道内低流量的情况下。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，但其表达的起始因子和信号传导机制（以及这些炎症介质在静脉壁适应中的生物学意义）在很大程度上仍然未知。我们小组先前的研究直接涉及促炎细胞因子TNF-α和抗炎细胞因子IL-10的产生，它们调节动脉壁对壁剪切力变化的适应。在最近的工作中，我们证明了特定的时间和流量依赖性细胞因子的签名在早期动脉化静脉移植。在低流量移植物中，TNF-α表达在24小时内被诱导近200倍，随后发生强烈的内膜增生，而高流量促进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向前推进：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和细胞增殖增加）发展新生内膜增生。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解剖信号通路。在差流环境下，TNF-α信号传导将通过可溶性受体、腺相关病毒（AAV）递送的TNF受体同源物、特异性p55或p75 TNF受体抗体或TNF-α转化酶抑制的抑制来定义。2)IL-10的产生通过减少炎性白细胞浸润、肌成纤维细胞增殖和下调TNF-α的产生来保护静脉移植物免受过度的闭塞性壁适应。将检查IL-10敲除小鼠的静脉移植物，以及用外源性IL-10（药理学和AV vIL-10）处理后的导管。 基于申请人在研究培训期间获得的新知识和技能，该初始独立提案的基本设计是将基本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的策略（草案耐久性）。