Role of mast cells in abdominal aortic aneurysms

描述(由申请人提供)：肥大细胞(MC)被认为是通过释放细胞质颗粒而引发过敏反应的基本效应细胞，其内容促进致敏时的过敏性炎症。最近的生化和组织学观察表明，MC参与了血液中白细胞的募集、平滑肌细胞(SMC)/内皮细胞的增殖和凋亡、T淋巴细胞的迁移和激活以及血管生成，这些参与了腹主动脉瘤(AAA)、炎性疾病(涉及复杂的细胞-细胞相互作用、炎性细胞募集、细胞因子产生、免疫反应和基质重塑)的发病机制。虽然还没有研究表明AAA的形成是否需要MC，但MC在动脉粥样硬化中的作用早在半个多世纪前就被提出了。MCS出现在人类动脉粥样硬化瘤中。我们最近的初步数据首次证明，在人和小鼠的AAA病变中存在MC。巨噬细胞缺乏可阻止主动脉弹性蛋白酶灌流所致的小鼠AAA形成。虽然所有野生型(wt，n=11)小鼠都发生了AAA，但MC缺失小鼠(n=9)没有发生AAA。重要的是，MC脱颗粒的药理稳定有效地阻止了WT小鼠AAA的形成。来自wt小鼠(n=12)的骨髓来源的MC的重建，而不是来自IL-6缺乏的小鼠(n=5)的骨髓来源的MC，恢复了MC缺失小鼠的AAA表型，这表明MC及其促炎介质直接参与了AAA的形成。然而，由于缺乏这一领域的知识，也缺乏解释这些发现的分子机制研究，导致了一个中心假说：MCS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建，从而在AAA的发病机制中发挥重要作用。我们提出了三个具体目标来检验这一假说：1)。研究MC缺失是否影响AAA的进展；2)以确定MC衍生的介质在AAA发病机制中的重要作用；研究MC如何影响血管细胞生物学，并确定MC在体内对病变的主动脉重新募集的重要趋化因子。总之，这些实验路线应该提供体外和体内证据，证明AAA的形成是否需要MC，并可能从机制上解释MC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.