Hosaka Koji, Rojas Kelley, Fazal Hanain Z, Schneider Matheus B, Shores Jorma, Federico Vincent, McCord Matthew, Lin Li, Hoh Brian
From the Department of Neurosurgery, University of Florida, Gainesville.
Stroke. 2017 Apr;48(4):1052-1060. doi: 10.1161/STROKEAHA.116.015590. Epub 2017 Mar 14.
We have previously demonstrated that the local delivery of monocyte chemotactic protein-1 (MCP-1) via an MCP-1-releasing poly(lactic-co-glycolic acid)-coated coil promotes intra-aneurysmal tissue healing. In this study, we demonstrate that interleukin-6 (IL-6) and osteopontin are downstream mediators in the MCP-1-mediated aneurysm-healing pathway.
Murine carotid aneurysms were created in C57BL/6 mice. Drug-releasing coils (MCP-1, IL-6, and osteopontin) and control poly(lactic-co-glycolic acid) coils were created and then implanted into the aneurysms to evaluate their intra-aneurismal-healing capacity. To investigate the downstream mediators for aneurysm healing, blocking antibodies for IL-6 receptor and osteopontin were given to the mice implanted with the MCP-1-releasing coils. A histological analysis of both murine and human aneurysms was utilized to cross-validate the data.
We observed increased expression of IL-6 in MCP-1-coil-treated aneurysms and not in control-poly(lactic-co-glycolic acid)-only-treated aneurysms. MCP-1-mediated intra-aneurysmal healing is inhibited in mice given blocking antibody to IL-6 receptor. MCP-1-mediated intra-aneurysmal healing is also inhibited by blocking antibody to osteopontin. The role of IL-6 in intra-aneurysmal healing is in recruiting of endothelial cells and fibroblasts. Local delivery of osteopontin to murine carotid aneurysms via osteopontin-releasing coil significantly promotes intra-aneurysmal healing, but IL-6-releasing coil does not, suggesting that IL-6 cannot promote aneurysm healing independent of MCP-1. In the MCP-1-mediated aneurysm healing, osteopontin expression is dependent on IL-6; inhibition of IL-6 receptor significantly inhibits osteopontin expression in MCP-1-mediated aneurysm healing.
Our findings suggest that IL-6 and osteopontin are key downstream mediators of MCP-1-mediated intra-aneurysmal healing.
我们之前已经证明，通过释放单核细胞趋化蛋白-1（MCP-1）的聚乳酸-乙醇酸共聚物包被的弹簧圈进行局部递送，可促进动脉瘤内组织愈合。在本研究中，我们证明白细胞介素-6（IL-6）和骨桥蛋白是MCP-1介导的动脉瘤愈合途径中的下游介质。
在C57BL/6小鼠中制造小鼠颈动脉动脉瘤。制备释放药物的弹簧圈（MCP-1、IL-6和骨桥蛋白）和对照聚乳酸-乙醇酸共聚物弹簧圈，然后将其植入动脉瘤中，以评估它们的动脉瘤内愈合能力。为了研究动脉瘤愈合的下游介质，给植入释放MCP-1弹簧圈的小鼠注射IL-6受体和骨桥蛋白的阻断抗体。利用小鼠和人类动脉瘤的组织学分析对数据进行交叉验证。
我们观察到，在接受MCP-1弹簧圈治疗的动脉瘤中，IL-6表达增加，而在仅接受对照聚乳酸-乙醇酸共聚物治疗的动脉瘤中则没有增加。给予IL-6受体阻断抗体的小鼠中，MCP-1介导的动脉瘤内愈合受到抑制。骨桥蛋白阻断抗体也可抑制MCP-1介导的动脉瘤内愈合。IL-6在动脉瘤内愈合中的作用是募集内皮细胞和成纤维细胞。通过释放骨桥蛋白的弹簧圈将骨桥蛋白局部递送至小鼠颈动脉动脉瘤，可显著促进动脉瘤内愈合，但释放IL-6的弹簧圈则不能，这表明IL-6不能独立于MCP-1促进动脉瘤愈合。在MCP-1介导的动脉瘤愈合中，骨桥蛋白的表达依赖于IL-6；抑制IL-6受体可显著抑制MCP-1介导的动脉瘤愈合中骨桥蛋白的表达。
我们的研究结果表明，IL-6和骨桥蛋白是MCP-1介导的动脉瘤内愈合的关键下游介质。
