Role of mast cells in abdominal aortic aneurysms

描述（由申请人提供）：肥大细胞（MCs）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。最近的生化和组织学观察表明，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淋巴细胞迁移和活化以及血管生成，这对于腹主动脉瘤（AAA）的发病至关重要，包括复杂的细胞-细胞相互作用、炎症细胞募集、细胞因子产生、免疫反应和基质重塑。尽管目前还没有研究证实AAA的形成是否需要MCs，但半个多世纪前就有人提出了MCs在动脉粥样硬化中的作用。MCs出现在人类动脉粥样硬化中。我们最近的初步数据首次表明，人类和小鼠AAA病变中存在MCs。MCs缺乏对小鼠主动脉弹性蛋白酶灌注诱导的AAA形成有抑制作用。虽然所有野生型（wt, n=11）小鼠都发生了AAA，但MC-null小鼠（n=9）没有发生AAA。重要的是，MC脱颗粒的药理学稳定有效地阻断了wt小鼠AAA的形成。重建来自wt小鼠（n=12）的骨髓源性MCs，而不是来自il -6缺陷小鼠（n=5）的骨髓源性MCs，恢复了mc缺失小鼠的AAA表型，这表明MCs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，也缺乏分子机制的研究来解释这些发现，导致了一个中心假设：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塑，对AAA的发病至关重要。我们提出了三个具体目标来验证这一假设：1)检查MCs的缺失是否会损害AAA的进展；2).确定在AAA发病机制中重要的mc衍生介质；和3)。目的：研究MCs如何影响血管细胞生物学，并在体内鉴定出负责MCs向病变主动脉募集的重要趋化因子。总之，这些实验线应该提供体外和体内证据，证明AAA的形成是否需要MCs，以及MCs如何影响这种常见血管疾病的可能机制解释。

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.