Adventitial mast cells contribute to pathogenesis in the progression of abdominal aortic aneurysm
Adventitial mast cells contribute to pathogenesis in the progression of abdominal aortic aneurysm
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DOI：
10.1161/circresaha.108.173682
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发表时间：
2008-06-06
影响因子：
20.1
通讯作者：
Kitamura, Kazuo
中科院分区：
文献类型：
--
作者：
Tsuruda, Toshihiro;Kato, Johji;Kitamura, Kazuo
腹主动脉瘤（AAA）的组织学特征是内侧变性和不同程度的慢性外膜炎症，尽管动脉瘤发展的机制尚不清楚。在本研究中，我们通过对患者AAA组织的组织学研究，以及介入性动物和细胞培养实验来探讨肥大细胞在AAA发病机制中的作用，发现人AAA外介质或外膜肥大细胞数量增加，细胞数量与AAA直径呈正相关。在对照组（+/+）大鼠中，在主动脉周围应用氯化钙（CaCl2）治疗后，可以看到主动脉动脉瘤扩张，但在肥大细胞缺陷突变的Ws/Ws大鼠中没有看到。AAA的形成伴随着肥大细胞、T淋巴细胞的积累和基质金属蛋白酶9的活化，主动脉组织中弹性蛋白水平降低和血管生成增强，但这些变化在Ws/Ws大鼠中要比对照组少得多。同样，载脂蛋白e缺乏小鼠的动脉瘤主动脉外膜也有肥大细胞的积累和活化。曲尼司特（肥大细胞脱颗粒抑制剂）的药理学干预可以减轻这些啮齿动物模型中的AAA发展。在细胞培养实验中，肥大细胞直接增强单核/巨噬细胞产生的基质金属蛋白酶9的活性。综上所述，这些数据表明，外基质肥大细胞在AAA的进展中起着关键作用。
Abdominal aortic aneurysm (AAA) is histologically characterized by medial degeneration and various degrees of chronic adventitial inflammation, although the mechanisms for progression of aneurysm are poorly understood. In the present study, we carried out histological study of AAA tissues of patients, and interventional animal and cell culture experiments to investigate a role of mast cells in the pathogenesis of AAA. The number of mast cells was found to increase in the outer media or adventitia of human AAA, showing a positive correlation between the cell number and the AAA diameter. Aneurysmal dilatation of the aorta was seen in the control (+/+) rats following periaortic application of calcium chloride (CaCl2) treatment but not in the mast cell-deficient mutant Ws/Ws rats. The AAA formation was accompanied by accumulation of mast cells, T lymphocytes and by activated matrix metalloproteinase 9, reduced elastin levels and augmented angiogenesis in the aortic tissue, but these changes were much less in the Ws/Ws rats than in the controls. Similarly, mast cells were accumulated and activated at the adventitia of aneurysmal aorta in the apolipoprotein E-deficient mice. The pharmacological intervention with the tranilast, an inhibitor of mast cell degranulation, attenuated AAA development in these rodent models. In the cell culture experiment, a mast cell directly augmented matrix metalloproteinase 9 activity produced by the monocyte/macrophage. Collectively, these data suggest that adventitial mast cells play a critical role in the progression of AAA.