Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice
Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice
复制标题
DOI：
10.1172/jci31311
复制
发表时间：
2007-11-01
影响因子：
15.9
通讯作者：
Shil, Guo-Ping
中科院分区：
文献类型：
--
作者：
Sun, Jiusong;Sukhova, Galina K.;Shil, Guo-Ping
腹主动脉瘤（AAA）是一种炎症性疾病，涉及白细胞募集、免疫反应、炎性细胞因子产生、血管重塑、新血管形成和血管细胞凋亡，所有这些都有助于主动脉扩张。这项研究表明，肥大细胞，在人类过敏性免疫的关键参与者，参与AAA的发病机制在小鼠中。肥大细胞被发现积累在小鼠AAA病变。肥大细胞缺陷型Kit（W-sh）/Kit（W-sh）小鼠未能发生由弹性蛋白酶灌注或主动脉周围化学损伤引起的AAA。Kit（W-sh）/Kit（W-sh）小鼠主动脉扩张和内弹性膜降解减少;巨噬细胞、CD 3（+）T淋巴细胞、SMC、凋亡细胞和CD 31（+）微血管数量减少;主动脉组织IL-6和IFN-γ水平降低。通过C48/80注射激活WT小鼠中的肥大细胞导致AAA生长增强，而用色甘酸钠稳定肥大细胞减少AAA形成。机制研究表明，肥大细胞参与血管生成，主动脉平滑肌细胞凋亡，基质降解蛋白酶的表达。用来自WT或TNF-α（-/-）小鼠而非IL-6（-/-）或IFN-γ（-/-）小鼠的骨髓源性肥大细胞重建Kit（W-sh）/Kit（W-sh）小鼠，导致对AAA形成的易感性恢复。这些结果表明，肥大细胞通过释放促炎细胞因子IL-6和IFN-γ参与小鼠AAA的发病机制，这可能诱导主动脉SMC凋亡、基质降解蛋白酶表达和血管壁重塑，这是动脉瘤的重要标志。
Abdominal aortic aneurysm (AAA), an inflammatory disease, involves leukocyte recruitment, immune responses, inflammatory cytokine production, vascular remodeling, neovascularization, and vascular cell apoptosis, all of which contribute to aortic dilatation. This study demonstrates that mast cells, key participants in human allergic immunity, participate in AAA pathogenesis in mice. Mast cells were found to accumulate in murine AAA lesions. Mast cell-deficient Kit(W-sh)/Kit(W-sh) mice failed to develop AAA elicited by elastase perfusion or periaortic chemical injury. Kit(W-sh)/Kit(W-sh) mice had reduced aortic expansion and internal elastic lamina degradation; decreased numbers of macrophages, CD3(+) T lymphocytes, SMCs, apoptotic cells, and CD31(+) microvessels; and decreased levels of aortic tissue IL-6 and IFN-gamma. Activation of mast cells in WT mice via C48/80 injection resulted in enhanced AAA growth while mast cell stabilization with disodium cromoglycate diminished AAA formation. Mechanistic studies demonstrated that mast cells participated in angiogenesis, aortic SMC apoptosis, and matrix-degrading protease expression. Reconstitution of Kit(W-sh)/Kit(W-sh) mice with bone marrow-derived mast cells from WT or TNF-alpha(-/-) mice, but not from IL-6(-/-) or IFN-gamma(-/-) mice, caused susceptibility to AAA formation to be regained. These results demonstrate that mast cells participate in AAA pathogenesis in mice by releasing pro-inflammatory cytokines IL-6 and IFN-gamma, which may induce aortic SMC apoptosis, matrix-degrading protease expression, and vascular wall remodeling, important hallmarks of arterial aneurysms.