Genetic and pharmacologic disruption of interleukin-1β signaling inhibits experimental aortic aneurysm formation.
Genetic and pharmacologic disruption of interleukin-1β signaling inhibits experimental aortic aneurysm formation.
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DOI：
10.1161/atvbaha.112.300432
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发表时间：
2013-02
期刊：
影响因子：
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通讯作者：
Ailawadi G
中科院分区：
文献类型：
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作者：
Johnston WF;Salmon M;Su G;Lu G;Stone ML;Zhao Y;Owens GK;Upchurch GR Jr;Ailawadi G
腹主动脉瘤(AAA)很常见，但其确切发病机制尚不清楚，目前尚无特效的药物治疗方法。我们试图在实验性腹主动脉瘤模型中评估白细胞介素1受体(IL-1β，IL-1β)和白介素1受体(IL-1R)，以寻找治疗腹主动脉瘤的新靶点。与生理盐水灌流相比，8-12周龄雄性C57BL/6小鼠腹主动脉弹性酶灌流(WT)后IL-1β基因和蛋白水平显著升高。IL-1β(IL-1βKO)或IL-1R(IL-1R KO)基因缺失的小鼠经弹性酶灌流后，对AAA的形成有明显的保护作用，IL-1βKO和IL-1R KO的最大主动脉扩张分别为38.0%±5.5%和52.5%±4.6%，而WT组为89.4%±4.0%(p<；0.005)。相应地，与WT相比，IL-1βKO和IL-1R KO的主动脉巨噬细胞和中性粒细胞染色减少，弹性蛋白保留更多。在接受IL-1R拮抗剂Anakinra递增剂量治疗的WT小鼠中，最大主动脉扩张呈剂量依赖性下降(R=−0.676，p<；0.0005)。Anakinra剂量的增加与巨噬细胞染色和弹性蛋白断裂的减少相关。最后，在AAA启动后3天或7天，用弹性酶治疗WT小鼠，显示出显著的保护作用，防止AAA进展，并与对照组小鼠相比，降低了主动脉扩张。IL-1β在腹主动脉瘤的发生和发展中起关键作用，通过基因缺失或受体拮抗的方式中和IL-1β可抑制实验性腹主动脉瘤的形成。阻断IL-1β信号为治疗腹主动脉瘤提供了新的途径。
Abdominal aortic aneurysms (AAAs) are common, but their exact pathogenesis remains unknown and no specific medical therapies are available. We sought to evaluate interleukin-1β (IL-1β) and interleukin-1 receptor (IL-1R) in an experimental AAA model to identify novel therapeutic targets for AAA treatment. IL-1β mRNA and protein levels were significantly elevated in abdominal aortas of 8-12 week old male C57Bl/6 mice following elastase aortic perfusion (WT) compared to saline perfusion. Mice with genetic deletion of IL-1β (IL-1β KO) or IL-1R (IL-1R KO) that underwent elastase perfusion demonstrated significant protection against AAA formation, with maximal aortic dilations of 38.0±5.5% for IL-1β KO and 52.5±4.6% for IL-1R KO compared to 89.4±4.0% for WT mice (p<0.005). Correspondingly, IL-1β KO and IL-1R KO aortas had reduced macrophage and neutrophil staining with greater elastin preservation compared to WT. In WT mice pretreated with escalating doses of the IL-1R antagonist anakinra, there was a dose-dependent decrease in maximal aortic dilation (R=−0.676, p <0.0005). Increasing anakinra doses correlated with decreasing macrophage staining and elastin fragmentation. Lastly, WT mice treated with anakinra 3 or 7 days following AAA initiation with elastase demonstrated significant protection against AAA progression and had decreased aortic dilation compared to control mice. IL-1β is critical for AAA initiation and progression, and IL-1β neutralization through genetic deletion or receptor antagonism attenuates experimental AAA formation. Disrupting IL-1β signaling offers a novel pathway for AAA treatment.