Contribution of Mast Cells to Cerebral Aneurysm Formation
Contribution of Mast Cells to Cerebral Aneurysm Formation
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DOI：
10.2174/156720210791184916
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发表时间：
2010-05-01
影响因子：
2.1
通讯作者：
Miyamoto, Susumu
中科院分区：
文献类型：
--
作者：
Ishibashi, Ryota;Aoki, Tomohiro;Miyamoto, Susumu
脑动脉瘤(CA)发病率高，可导致致命性蛛网膜下腔出血。虽然CA是一种重要的社会疾病，但由于CA形成的详细机制尚不清楚，目前除外科手术外，尚无其他药物治疗CA。根据最近的研究，我们认为CA是一种慢性动脉壁炎症性疾病，多种炎症相关因素参与了其发病机制。肥大细胞是公认的与过敏性炎症相关的主要炎症细胞。肥大细胞含有大量含有各种细胞因子的胞质颗粒。最近的研究表明，肥大细胞通过脱颗粒和细胞因子的释放参与了各种血管疾病的发生。在本研究中，我们利用一个实验性的大鼠模型，研究了肥大细胞在CA发病机制中的作用。在CA形成过程中，CA壁中的肥大细胞数量显著增加。肥大细胞脱颗粒抑制剂通过抑制慢性炎症反应，如核因子-kappaB活化、巨噬细胞浸润和单核细胞趋化蛋白-1、基质金属蛋白酶(MMPs)和白介素1的表达，有效地抑制诱导的CA的大小和中层变薄。此外，体外研究表明，肥大细胞脱颗粒可诱导原代培养的大鼠颅内动脉平滑肌细胞表达和激活基质金属蛋白酶-2、-9和诱导型一氧化氮合酶。提示肥大细胞通过诱导炎症反应参与CA的发病，肥大细胞脱颗粒抑制剂可作为治疗CA的药物。
Cerebral aneurysm (CA) has a high prevalence and causes a fatal subarachnoid hemorrhage. Although CA is a socially important disease, there are currently no medical treatments for CA, except for surgical procedures, because the detailed mechanisms of CA formation remain unclear. From recent studies, we propose that CA is a chronic inflammatory disease of the arterial walls and various inflammation-related factors participate in its pathogenesis. Mast cells are well recognized as major inflammatory cells related to allergic inflammation. Mast cells have numerous cytoplasmic granules that contain various cytokines. Recent studies have revealed that mast cells contribute to various vascular diseases through degranulation and release of cytokines. In the present study, we examined the role of mast cells in the pathogenesis of CA using an experimental rat model. The number of mast cells was significantly increased in CA walls during CA formation. Inhibitors of mast cell degranulation effectively inhibited the size and medial thinning of induced CA through the inhibition of chronic inflammation, as evaluated by nuclear factor-kappa B activation, macrophage infiltration, and the expression of monocyte chemoattractant protein-1, matrix metalloproteinases (MMPs), and interleukin-1. Furthermore, an in vitro study revealed that the degranulation of mast cells induced the expression and activation of MMP-2, -9, and inducible nitric oxide synthase in primary cultured smooth muscle cells from rat intracranial arteries. These results suggest that mast cells contribute to the pathogenesis of CA through the induction of inflammation and that inhibitors of mast cell degranulation can be therapeutic drugs for CA.