Monocyte chemotactic protein-1 promotes inflammatory vascular repair of murine carotid aneurysms via a macrophage inflammatory protein-1α and macrophage inflammatory protein-2-dependent pathway.
Monocyte chemotactic protein-1 promotes inflammatory vascular repair of murine carotid aneurysms via a macrophage inflammatory protein-1α and macrophage inflammatory protein-2-dependent pathway.
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DOI：
10.1161/circulationaha.111.036061
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发表时间：
2011-11-15
期刊：
影响因子：
37.8
通讯作者：
Scott EW
中科院分区：
文献类型：
--
作者：
Hoh BL;Hosaka K;Downes DP;Nowicki KW;Fernandez CE;Batich CD;Scott EW
高达5%的人口可能患有脑动脉瘤，如果脑动脉瘤破裂，死亡率超过50%，超过三分之一的幸存者是依赖性的。在破裂之前检测到的脑动脉瘤可以进行治疗以防止破裂，或者破裂的动脉瘤可以进行治疗以防止再次破裂。脑动脉瘤的血管内弹簧圈栓塞术是某些动脉瘤的治疗选择;然而，高达四分之一的动脉瘤可能复发。不复发的弹簧圈栓塞动脉瘤的特征是炎性动脉瘤内组织愈合;因此，我们研究了这一过程的生物学，特别是单核细胞趋化蛋白-1（MCP-1）的作用，MCP-1是一种已知的组织愈合细胞因子。我们创建了具有PLGA涂层的弹簧圈，其以3种不同剂量（100 μg/mL; 1 mg/mL;和10 mg/mL）释放MCP-1，并在鼠颈动脉瘤模型中进行了对动脉瘤内组织愈合影响的剂量反应研究。然后，我们证明了MCP-1（100 μg/mL）释放弹簧圈比裸铂或仅PLGA弹簧圈显著促进更大的动脉瘤组织向内生长。我们发现，MCP-1招募成纤维细胞，巨噬细胞，平滑肌细胞和内皮细胞在体外的迁移，在细胞迁移试验;和在体内，在小鼠颈动脉瘤。使用gfp骨髓移植嵌合小鼠，我们证明MCP-1募集的成纤维细胞和巨噬细胞来自骨髓。我们证明这种MCP-1介导的血管炎性修复是通过巨噬细胞炎性蛋白-1 α（MIP-1α）和巨噬细胞炎性蛋白-2（MIP-2）依赖的途径发生的。细胞因子阵列分析显示小鼠动脉瘤释放的MCP-1可显著上调MIP-1α和MIP-2的表达。用拮抗剂抗体阻断MIP-1α和MIP-2可显著降低MCP-1介导的瘤内组织愈合。我们的研究结果表明，MCP-1在MIP-1α和MIP-2依赖性途径中促进炎性膀胱内组织愈合中具有关键作用。
Up to 5% of the population may have a brain aneurysm, and if the brain aneurysm ruptures, there is greater than 50% mortality, and more than onethird of survivors are dependent. Brain aneurysms detected before rupture can be treated to prevent rupture, or ruptured aneurysms can be treated to prevent re-rupture. Endovascular coiling of brain aneurysms is the treatment of choice for some aneurysms; however, up to one quarter of aneurysms may recur. The coiled aneurysms that do not recur are characterized by inflammatory intra-aneurysmal tissue healing; therefore, we studied the biology of this process, specifically, the role of monocyte chemotactic protein-1 (MCP-1), a cytokine known for tissue healing. We created coils with a PLGA coating that released MCP-1 at 3 different doses (100 μg/mL; 1 mg/mL; and 10 mg/mL) and performed a dose-response study for effect on intra-aneurysmal tissue healing in a murine carotid aneurysm model. We then demonstrated MCP-1(100 μg/mL)-releasing coils promote significantly greater aneurysm tissue ingrowth than bare platinum or PLGA-only coils. We show that MCP-1 recruits the migration of fibroblasts, macrophages, smooth muscle cells, and endothelial cells in vitro, in cell migration assays; and in vivo, in murine carotid aneurysms. Using gfp bone marrow transplant chimeric mice, we demonstrate that the MCP-1-recruited fibroblasts and macrophages are derived from the bone marrow. We demonstrate that this MCP-1-mediated vascular inflammatory repair occurs via amacrophage inflammatory protein-1α (MIP-1α) and macrophage inflammatory protein-2 (MIP-2)-dependent pathway. MCP-1 released from coiled murine aneurysms causes significant upregulation of MIP-1α and MIP-2 expression by cytokine array assay. Blocking MIP-1α and MIP-2 with antagonist antibody causes significant decrease in MCP-1-mediated intra-aneurysmal tissue healing. Our findings suggest that MCP-1 has a critical role in promoting inflammatory intra-aneurysmal tissue healing in a MIP-1α and MIP-2-dependent pathway.