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: 7756800
• 负责人: C KEITH OZAKI
• 金额: $ 27.54万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 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/7756800
• 关键词: Aftercare; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Arterial Occlusive Diseases; Arthritis; Attention; Attenuated; Autologous; Biology; Blood Vessels; Bypass; Cell Proliferation; Cells; Coronary; Cytokine Signaling; Dependovirus; Development; Disease; Down-Regulation; Environment; Enzyme Inhibition; Evidence based treatment; Facility Construction Funding Category; Failure; Future; Hand; Homologous Gene; Hour; Hyperplasia; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-1; Interleukin-10; Intervention; Knockout Mice; Knowledge; Laboratories; Leukocytes; Link; Lower Extremity; Mediating; Mediator of activation protein; Membrane; Methods; Mus; Myofibroblast; Natural History; Operative Surgical Procedures; Pathologic; Pathology; Pathway interactions; Patients; Poxviridae; Process; Production; Receptor Signaling; Research; Research Personnel; Research Training; Rheumatoid Arthritis; Role; Sepsis; Signal Pathway; Signal Transduction; System; TNF gene; TNF-alpha converting enzyme; Testing; Time; Translating; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Veins; Viral; Work; base; body system; cell motility; cytokine; cytokine therapy; design; exhaust; graft failure; human MPP1 protein; human TNF protein; improved; in vivo; in vivo Model; inhibitor/antagonist; insight; knowledge base; mRNA Expression; programs; protective effect; receptor; response; skills; transcriptional coactivator p75

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)： 外科静脉搭桥术失败的主要原因是新生内膜增生，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，但其表达的启动因素和信号机制(以及这些炎性介质在静脉壁适应中的生物学意义)在很大程度上仍不清楚。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的产生在调节动脉壁对壁剪切力变化的适应性中。在最近的工作中，我们展示了早期动脉化静脉移植物中特定的时间和血流依赖的细胞因子特征。低流量移植物在24小时内可诱导近200倍的肿瘤坏死因子-α的表达，随后发生强烈的内膜增生，而高流量移植物可延迟诱导IL-10mRNA的表达，这似乎对闭塞适应具有保护作用。这项建议通过检验两个相互关联的机制假说来推进：1)静脉移植物通过低剪切力诱导的促炎细胞因子驱动的机制(通过p55受体的可溶性肿瘤坏死因子-α信号，导致白细胞介导的炎症增强和细胞增殖)导致新生内膜增生。通过研究缺乏可溶性肿瘤坏死因子-α或p55或p75受体的小鼠的静脉移植，信号通路将被剖析。在不同的流动环境下，可通过抑制可溶性受体、腺相关病毒(AAV)传递的肿瘤坏死因子受体同系物、特异性p55或p75肿瘤坏死因子受体抗体或抑制肿瘤坏死因子-α转换酶来确定肿瘤坏死因子-α信号转导。2)IL-10的产生通过减少炎性白细胞的浸润、肌成纤维细胞的增殖和下调TNF-α的产生来保护移植静脉免受过度旺盛的闭塞壁适应。将检查来自IL-10基因敲除小鼠的静脉移植物，以及外源IL-10(药理学和AAVVIL-10)处理后的管道。 基于申请人在研究培训中获得的新知识和技能，这项初步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)。