Cytokine Driven Mechanisms of Vein Graft Failure

外科静脉搭桥术失败的主要原因是新生内膜增生，尤其是在 设置管道内的低流量。炎症是这一过程的病理特征。而当 细胞因子与静脉移植失败有关，其启动因素和信号机制 表达(以及这些炎症介质在静脉壁适应中的生物学意义) 在很大程度上仍然不为人知。我们小组之前的研究直接涉及到前两种基因的产生 炎性细胞因子和抗炎细胞因子IL-10在动脉壁适应性调节中的作用 墙体剪力的变化。在最近的工作中，我们展示了特定的时间和流量依赖的细胞因子。 早期动脉化静脉移植物的征象。在24小时内，肿瘤坏死因子-C_1的表达几乎增加了200倍。 低流量移植物随后发展为强健的内膜增生，而高流量移植物则促进延迟的 诱导IL-10mRNA的表达，似乎对闭塞适应具有保护作用。 这一建议通过检验两个相互关联的机械假说来推进：1)静脉移植物的形成 低剪切力诱导的促炎细胞因子驱动的新生内膜增生 机制(通过p55受体的可溶性肿瘤坏死因子-a信号，导致白细胞增强 炎症和细胞增殖增加)。信号通路将通过研究静脉来解剖 缺乏可溶性肿瘤坏死因子-α或p55或p75受体的小鼠的移植物。在不同流动环境下，肿瘤坏死因子- (_信号将通过腺相关病毒(AAV)递送的可溶性受体的抑制来定义 肿瘤坏死因子受体同源物、特异性p55或p75肿瘤坏死因子受体抗体或肿瘤坏死因子转换酶 抑制力。2)IL-10的产生通过以下途径保护静脉移植物免受过度旺盛的闭塞壁适应 减少炎性白细胞浸润，肌成纤维细胞增殖，下调肿瘤坏死因子-1 C？生产。将检查IL-10基因敲除小鼠的静脉移植物，以及治疗后的管道 外源性IL-10(药理学和AAVIL-10)。 根据申请人在研究培训期间获得的新知识和技能，基本 这个最初的独立提案的设计是将基础细胞因子生物学转移到血管生物学，以及 通过新的机制洞察，将这些findin.qs转化为strate.qies，以提高静脉()筏的耐久性。

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 pro- inflammatory cytokine TNF-o_ 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-c_ 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-a 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-_, or the p55 or p75 receptor. Under differential flow environments, TNF- (_ 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-o_ 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- c¿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 throu.qh new mechanistic insights, translate these findin.qs into strate.qies to improve vein (]raft durability.