Role of mast cells in abdominal aortic aneurysms

描述（由申请方提供）：肥大细胞（MC）被认为是通过释放胞质颗粒引发过敏反应的重要效应细胞，其内容物在致敏后促进过敏性炎症。最近的生物化学和组织学观察表明，MCs参与血源性白细胞募集，平滑肌细胞（SMC）/内皮细胞增殖和凋亡，T淋巴细胞迁移和激活，血管生成，腹主动脉瘤（AAA）的发病机制是必不可少的，炎症性疾病涉及复杂的细胞-细胞相互作用，炎症细胞募集，细胞因子的产生，免疫反应，和基质重塑。虽然还没有研究来检查AAA的形成是否需要MC，但在世纪前就提出了MC在动脉粥样硬化中的作用。MC出现在人类动脉粥样硬化中。我们最近的初步数据表明，第一次，在人类和小鼠AAA病变的MC的存在。MCs缺乏可抑制腹主动脉弹性蛋白酶灌流诱导的AAA形成。虽然所有野生型（wt，n=11）小鼠均发生AAA，但MC-缺失小鼠（n=9）均未发生AAA。重要的是，MC脱粒的药理学稳定有效地阻断了野生型小鼠中AAA的形成。来自野生型小鼠（n=12）而非来自IL-6缺陷型小鼠（n=5）的骨髓来源的MC的重建恢复了MC缺失型小鼠中的AAA表型，表明MC及其促炎介质直接参与AAA形成。然而，缺乏在这一领域的知识和缺乏分子机制的研究来解释这些发现导致了一个中心的假设，即：MC是必不可少的AAA发病机制，通过释放促炎介质直接参与血管细胞增殖，凋亡，血管生成和动脉壁重塑。我们提出了三个具体目标来检验这一假设：1）。检查MC的缺失是否损害AAA的进展; 2）.鉴定对AAA发病机制重要的MC衍生介质;和3）.研究MC如何影响血管细胞生物学，并确定重要的趋化因子，负责MC招募到患病的血管在体内。总之，这些实验线应提供在体外和体内的证据，是否AAA的形成需要MC和可能的机制解释MC可能如何影响这种常见的血管疾病。

DESCRIPTION (provided by applicant): Mast cells (MCs) are recognized as essential effecter cells in the elicitation of the allergic response by releasing cytoplasmic granules, whose contents promote allergic inflammation upon sensitization. Recent biochemical and histological observations suggested that MCs participate in blood-borne leukocyte recruitment, smooth muscle cell (SMC)/endothelial cell proliferation and apoptosis, T-lymphocyte migration and activation, and angiogenesis, essential for the pathogenesis of abdominal aortic aneurysms (AAA), inflammatory disease involving sophisticated cell-cell interaction, inflammatory cell recruitment, cytokine production, immune responses, and matrix remodeling. Although no study has yet been carried out to examine whether AAA formation requires MCs, a role for MCs in atherosclerosis was proposed more than half a century ago. MCs appear in human atheromata. Our recent preliminary data demonstrated, for the first time, the presence of MCs in human and mouse AAA lesions. Deficiency of MCs prevented mice from AAA formation induced by aortic elastase perfusion. While all wild-type (wt, n=11) mice developed AAA, none of the MC-null mice (n=9) did. Importantly, pharmacological stabilization of MC degranulation blocked effectively AAA formation in wt mice. Reconstitution of bone marrow-derived MCs from wt mice (n=12), but not those from IL-6-deficient mice (n=5), restored the AAA phenotypes in MC-null mice, suggesting a direct participation of MCs and their proinflammatory mediators in AAA formation. However, a lack of knowledge in this field and the absence of studies of molecular mechanisms to explain these findings led to a central hypothesis that: MCs are essential to AAA pathogenesis by releasing proinflammatory mediators to participate directly in vascular cell proliferation, apoptosis, angiogenesis, and arterial wall remodeling. We propose three specific aims to test this hypothesis: 1). to examine whether absence of MCs impairs the progression of AAA; 2). to identify MC-derived mediators important to the AAA pathogenesis; and 3). To investigate how MCs affect vascular cell biology, and to identify important chemokines responsible for MC recruitment to the diseased aortae in vivo. Together, these lines of experiments should provide both in vitro and in vivo evidence of whether AAA formation requires MCs and possible mechanistic explanations of how MCs might influence this common vascular disorder.