The oral administration of clarithromycin prevents the progression and rupture of aortic aneurysm
The oral administration of clarithromycin prevents the progression and rupture of aortic aneurysm
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DOI：
10.1016/j.jvs.2017.12.047
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发表时间：
2018-12
影响因子：
4.3
通讯作者：
W. Uchida;Y. Narita;A. Yamawaki-Ogata;Y. Tokuda;M. Mutsuga;K. Fujimoto;T. Abe;H. Oshima;A. Usui
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文献类型：
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作者：
W. Uchida;Y. Narita;A. Yamawaki-Ogata;Y. Tokuda;M. Mutsuga;K. Fujimoto;T. Abe;H. Oshima;A. Usui
目的主动脉动脉瘤（AA）的发病机制与主动脉壁慢性炎症相关，并伴有基质金属蛋白酶（MMPs）水平升高。克拉霉素（Clarithromycin， CAM）有抑制MMP活性的报道。在本研究中，我们研究了CAM是否能阻止AA的形成和破裂。方法28 ~ 30周龄的载脂蛋白e缺陷小鼠灌胃血管紧张素II 28 d。每天口服CAM （100 mg/kg/d）或生理盐水（作为对照）（CAM组，n = 13；对照组，n = 13）。给药期结束后，测定大鼠主动脉直径、弹性蛋白含量、巨噬细胞浸润、MMP水平和炎症因子水平，包括核因子κB （NF-κB）水平。结果CAM组大鼠主动脉直径明显减小（P< 0.001）。CAM组无破裂死亡，对照组5例（38%），差异有统计学意义（P< 0.01）。CAM显著抑制主动脉弹性蛋白降解（56.3% vs 16.5%， P< 0.001），降低炎性巨噬细胞浸润（0.05 vs 0.16， P< 0.01）。与对照组相比，CAM组MMP-2、MMP-9酶活性显著降低（MMP-2, 0.15 vs 0.56 [P< 0.01]; MMP-9, 0.12 vs 0.60 [P< 0.01]），白细胞介素1β （346.6 vs 1066.0， P< 0.05）、白细胞介素6 （128.4 vs 346.2， P< 0.05）、NF-κB磷酸化水平降低（0.3 vs 2.0， P< 0.01）。结论诈骗通过抑制炎性巨噬细胞浸润、降低MMP-2和MMP-9活性、抑制弹性蛋白降解（与抑制NF-κB磷酸化有关）来抑制AA的进展和破裂。
ObjectiveThe pathogenesis of aortic aneurysm (AA) is associated with chronic inflammation in the aortic wall with increased levels of matrix metalloproteinases (MMPs). Clarithromycin (CAM) has been reported to suppresses MMP activity. In this study, we investigated whether CAM could prevent the formation and rupture of AA.MethodsMale apolipoprotein E-deficient mice (28-30 weeks of age) were infused with angiotensin II for 28 days. CAM (100 mg/kg/d) or saline (as a control) was administered orally to the mice every day (CAM group, n = 13; control group, n = 13). After the administration period, the aortic diameter, elastin content, macrophage infiltration, MMP levels, and levels of inflammatory cytokines, including nuclear factor κB (NF-κB), were measured.ResultsThe aortic diameter was significantly suppressed in the CAM group (P< .001). No rupture death was observed in the CAM group in contrast to five deaths (38%) in the control group (P< .01). CAM significantly suppressed the degradation of aortic elastin (56.3% vs 16.5%;P< .001) and decreased the infiltration of inflammatory macrophages (0.05 vs 0.16;P< .01). Compared with the controls, the enzymatic activity of MMP-2 and MMP-9 was significantly reduced in the CAM group (MMP-2, 0.15 vs 0.56 [P< .01]; MMP-9, 0.12 vs 0.60 [P< .01]), and the levels of interleukin 1β (346.6 vs 1066.0;P< .05), interleukin 6 (128.4 vs 346.2;P< .05), and phosphorylation of NF-κB were also decreased (0.3 vs 2.0;P< .01).ConclusionsCAM suppressed the progression and rupture of AA through the suppression of inflammatory macrophage infiltration, a reduction in MMP-2 and MMP-9 activity, and the inhibition of elastin degradation associated with the suppression of NF-κB phosphorylation.