Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model.
Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model.
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DOI：
10.1016/j.jvs.2018.05.206
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发表时间：
2018-12
影响因子：
4.3
通讯作者：
Conte MS
中科院分区：
文献类型：
--
作者：
Wu B;Werlin EC;Chen M;Mottola G;Chatterjee A;Lance KD;Bernards DA;Sansbury BE;Spite M;Desai TA;Conte MS
炎症是静脉移植物内新生内膜过度增生的关键驱动因素。最近的研究表明，由 omega-3 多不饱和脂肪酸生物合成的专门的促消退脂质介质，例如消退素 D1 (RvD1)，可积极协调炎症消退过程。我们研究了在兔静脉移植模型中局部血管周围递送 RvD1 的效果。通过吻合套囊技术将同侧颈静脉作为颈动脉介入移植物植入新西兰白兔（3-4 kg；N = 80）中。使用 25% Pluronic F127 凝胶（Sigma-Aldrich，圣路易斯，密苏里州）或薄双层聚（乳酸-乙醇酸）（PLGA）薄膜，以血管周围的方式将 RvD1（1 μg）递送至静脉旁路移植物。无处理（仅旁路）和载有载体的 Pluronic 凝胶或 PLGA 薄膜作为对照。 3天后通过液相色谱-串联质谱法评估RvD1向静脉组织的递送。通过免疫组织化学评估总白细胞浸润、巨噬细胞浸润和细胞增殖。对搭桥后 28 天收获的移植物进行弹性蛋白和三色染色，以评估新内膜增生和静脉移植物重塑。血管周围治疗不影响移植物血栓形成率（23%）、主要伤口并发症（4%）或死亡率（3%）。 3 天后，与对照组相比，RvD1 治疗组的白细胞 (CD45) 和巨噬细胞 (RAM11) 浸润显着减少（减少 60%−72%；P < .01）。 3 天时，RvD1 处理的移植物的细胞增殖（Ki67 指数）也显着低于对照移植物（减少 40%−50%；P < .01）。用负载 RvD1 的凝胶治疗静脉移植物，与仅搭桥相比，在 28 天时新生内膜厚度减少了 61% (P < .001)，与载体凝胶相比，新生内膜厚度减少了 63% (P < .001)。与仅搭桥相比，加载 RvD1 的 PLGA 薄膜在 28 天时将新内膜形成减少了 50% (P < .001)。 RvD1 治疗还与 28 天时静脉移植物中胶原沉积的减少有关。在兔颈动脉绕道模型中，RvD1 的局部血管周围递送可减轻静脉移植物增生，且无相关毒性。这种效应似乎是由移植物内白细胞募集减少和细胞增殖减少介导的。在此静脉动脉化模型中，血管周围 PLGA 薄膜还可以通过生物力学支架提供保护。我们的研究进一步支持了专门的促溶解脂质介质（例如 D 系列溶解素）在调节血管损伤和修复中的潜在治疗作用。 （J Vasc Surg 2018；■：1–12。）自体静脉旁路移植是周围血管疾病血运重建最持久的方法；然而，中期和长期结果受到静脉移植物增生和相关静脉移植物失败的限制。内源性促溶解脂质介质（例如 resolvin D1）具有通过加速修复来减轻静脉移植物增生的潜力。这项研究为局部递送 resolvin D1 以减少炎症并改善静脉旁路移植术后的愈合反应提供了概念证明。
Inflammation is a key driver of excessive neointimal hyperplasia within vein grafts. Recent work demonstrates that specialized proresolving lipid mediators biosynthesized from omega-3 polyunsaturated fatty acids, such as resolvin D1 (RvD1), actively orchestrate the process of inflammation resolution. We investigated the effects of local perivascular delivery of RvD1 in a rabbit vein graft model. Ipsilateral jugular veins were implanted as carotid interposition grafts through an anastomotic cuff technique in New Zealand white rabbits (3–4 kg; N = 80). RvD1 (1 μg) was delivered to the vein bypass grafts in a perivascular fashion, using either 25% Pluronic F127 gel (Sigma-Aldrich, St. Louis, Mo) or a thin bilayered poly(lactic-co-glycolic acid) (PLGA) film. No treatment (bypass only) and vehicle-loaded Pluronic gels or PLGA films served as controls. Delivery of RvD1 to venous tissue was evaluated 3 days later by liquid chromatography-tandem mass spectrometry. Total leukocyte infiltration, macrophage infiltration, and cell proliferation were evaluated by immunohistochemistry. Elastin and trichrome staining was performed on grafts harvested at 28 days after bypass to evaluate neointimal hyperplasia and vein graft remodeling. Perivascular treatments did not influence rates of graft thrombosis (23%), major wound complications (4%), or death (3%). Leukocyte (CD45) and macrophage (RAM11) infiltration was significantly reduced in the RvD1 treatment groups vs controls at 3 days (60%−72% reduction; P < .01). Cellular proliferation (Ki67 index) was also significantly lower in RvD1-treated vs control grafts at 3 days (40%−50% reduction; P < .01). Treatment of vein grafts with RvD1-loaded gels reduced neointimal thickness at 28 days by 61% vs bypass only (P < .001) and by 63% vs vehicle gel (P < .001). RvD1-loaded PLGA films reduced neointimal formation at 28 days by 50% vs bypass only (P < .001). RvD1 treatment was also associated with reduced collagen deposition in vein grafts at 28 days. Local perivascular delivery of RvD1 attenuates vein graft hyperplasia without associated toxicity in a rabbit carotid bypass model. This effect appears to be mediated by both reduced leukocyte recruitment and decreased cell proliferation within the graft. Perivascular PLGA films may also impart protection through biomechanical scaffolding in this venous arterialization model. Our studies provide further support for the potential therapeutic role of specialized proresolving lipid mediators such as D-series resolvins in modulating vascular injury and repair. (J Vasc Surg 2018;■:1–12.) Autologous vein bypass grafts are the most durable means for revascularization in peripheral vascular disease; however, midterm and long-term outcomes are limited by vein graft hyperplasia with associated vein graft failure. Endogenous proresolving lipid mediators such as resolvin D1 have the potential to attenuate vein graft hyperplasia by accelerating repair. This study provides proof of concept for local delivery of resolvin D1 to reduce inflammation and to improve the healing response after vein bypass grafting.
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影响因子：
5
作者：
Makadia HK;Siegel SJ
通讯作者：
Siegel SJ
影响因子：
64.8
作者：
Chiang, Nan;Fredman, Gabrielle;Backhed, Fredrik;Oh, Sungwhan F.;Vickery, Thad;Schmidt, Birgitta A.;Serhan, Charles N.
通讯作者：
Serhan, Charles N.
影响因子：
3.4
作者：
Dai, Longsheng;Gao, Mingxin;Yu, Yang
通讯作者：
Yu, Yang
影响因子：
4.3
作者：
Causey, Marlin W.;Ahmed, Ayman;Conte, Michael S.
通讯作者：
Conte, Michael S.
影响因子：
6
作者：
El Kebir D;Filep JG
通讯作者：
Filep JG