HB-EGF-Promoted Airway Smooth Muscle Cells and Their Progenitor Migration Contribute to Airway Smooth Muscle Remodeling in Asthmatic Mouse
HB-EGF-Promoted Airway Smooth Muscle Cells and Their Progenitor Migration Contribute to Airway Smooth Muscle Remodeling in Asthmatic Mouse
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DOI：
10.4049/jimmunol.1402126
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发表时间：
2016-03-01
影响因子：
4.4
通讯作者：
Zhou, Jianying
中科院分区：
文献类型：
--
作者：
Wang, Qing;Li, Hequan;Zhou, Jianying
目前认为气道平滑肌细胞的增殖、迁移及其祖细胞的迁移是导致哮喘气道重塑的重要因素。肝素结合表皮生长因子（HB-EGF）是一种强有力的促分裂因子和趋化因子，可通过MAPK途径促进ASM细胞增殖。本研究从C57 BL/6小鼠中获得了原代ASM细胞及其祖细胞，并探讨了HB-EGF在这些细胞迁移中的作用及其机制。我们发现，重组HB-EGF（rHB-EGF）气管内滴注加速ASM层增厚在OVA诱导的哮喘小鼠。改良Boyden小室法显示，rHB-EGF以剂量依赖性方式促进ASM细胞迁移，哮喘小鼠ASM细胞的迁移能力比正常小鼠ASM细胞更强。rHB-EGF可刺激ASM细胞中ERK 1/2和p38的磷酸化，但迁移实验表明，只有表皮生长因子受体抑制剂（AG 1478）或p38抑制剂（SB 203580）能抑制rHB-EGF介导的ASM细胞迁移，而ERK 1/2抑制剂（PD 98059）则不能抑制rHB-EGF介导的ASM细胞迁移。肌动蛋白细胞骨架实验表明，rHB-EGF可通过激活p38，使平滑肌细胞肌动蛋白应力纤维解体，形成粘着斑。最后，气道滴注rHB-EGF促进了骨髓来源的平滑肌祖细胞的募集，这些细胞通过尾静脉转移，从循环迁移到气道。这些观察结果表明，ASM重塑哮喘可能是由于HB-EGF介导的ASM细胞及其祖细胞迁移，通过p38 MAPK依赖的肌动蛋白细胞骨架重塑。
The airway smooth muscle (ASM) cells' proliferation, migration, and their progenitor's migration are currently regarded as causative factors for ASM remodeling in asthma. Heparin-binding epidermal growth factor (HB-EGF), a potent mitogen and chemotactic factor, could promote ASM cell proliferation through MAPK pathways. In this study, we obtained primary ASM cells and their progenitors from C57BL/6 mice and went on to explore the role of HB-EGF in these cells migration and the underlying mechanisms. We found that recombinant HB-EGF (rHB-EGF) intratracheal instillation accelerated ASM layer thickening in an OVA-induced asthmatic mouse. Modified Boyden chamber assay revealed that rHB-EGF facilitate ASM cell migration in a dose-dependent manner and ASM cells from asthmatic mice had a greater migration ability than that from normal counterparts. rHB-EGF could stimulate the phosphorylation of ERK1/2 and p38 in ASM cells but further migration assay showed that only epidermal growth factor receptor inhibitor (AG1478) or p38 inhibitor (SB203580), but not ERK1/2 inhibitor (PD98059), could inhibit rHB-EGF-mediated ASM cells migration. Actin cytoskeleton experiments exhibited that rHB-EGF could cause actin stress fibers disassembly and focal adhesions formation of ASM cells through the activation of p38. Finally, airway instillation of rHB-EGF promoted the recruitment of bone marrow-derived smooth muscle progenitor cells, which were transferred via caudal vein, migrating into the airway from the circulation. These observations demonstrated that ASM remodeling in asthma might have resulted from HB-EGF-mediated ASM cells and their progenitor cells migration, via p38 MAPK-dependent actin cytoskeleton remodeling.