Allergy Center, Mie National Hospital, Tsu, Japan.
Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu, Japan.
Front Immunol. 2018 Sep 20;9:2163. doi: 10.3389/fimmu.2018.02163. eCollection 2018.
Airway remodeling is responsible for the progressive decline of lung function in bronchial asthma. Matrix metalloproteinase-2 and fibroblast-to-myofibroblast transition are involved in tissue remodeling. Here we evaluated whether eosinophils play a role in fibroblasts-to-myofibroblasts transition and in the expression of matrix metalloproteinase-2. We co-cultured human eosinophils with human fetal lung fibroblast-1 cells, assessed the expression of remodeling-associated molecules by immunoassays and polymerase-chain reaction, and eosinophils-mediated migration of human fetal lung fibroblast-1 cells using a Boyden chamber. To clarify the participation of matrix metalloproteinase-2 in airway remodeling we administered bone marrow-derived eosinophils by intra-tracheal route to transgenic mice overexpressing the human matrix metalloproteinase-2. The expression of α-smooth muscle actin significantly increased in human fetal lung fibroblast-1 cells co-cultured with human eosinophils compared to controls. There was enhanced expression of matrix metalloproteinase-2 during fibroblast-to-myofibroblast transition. An inhibitor of matrix metalloproteinases blocked eosinophils-associated fibroblast-to-myofibroblast transition and increased migration of fibroblasts. The human matrix metalloproteinase-2 transgenic mice receiving adoptive transfer of mouse eosinophils exhibited increased inflammation and advanced airway remodeling compared to wild type mice. This study demonstrated that eosinophils induce fibroblast-to-myofibroblast transition, secretion of matrix metalloproteinase-2, accelerated migration of fibroblasts, and promote matrix metalloproteinase-2-related airway remodeling. These findings provide a novel mechanistic pathway for eosinophil-associated airway remodeling in bronchial asthma.
气道重塑是导致支气管哮喘肺功能进行性下降的原因。基质金属蛋白酶-2 和纤维母细胞向肌纤维母细胞转化参与组织重塑。在这里，我们评估了嗜酸性粒细胞是否在纤维母细胞向肌纤维母细胞转化以及基质金属蛋白酶-2 的表达中发挥作用。我们将人嗜酸性粒细胞与人胎儿肺成纤维细胞-1 共培养，通过免疫测定和聚合酶链反应评估重塑相关分子的表达，并使用 Boyden 室评估嗜酸性粒细胞介导的人胎儿肺成纤维细胞-1 细胞迁移。为了阐明基质金属蛋白酶-2 在气道重塑中的参与，我们通过气管内途径向过表达人基质金属蛋白酶-2 的转基因小鼠给予骨髓来源的嗜酸性粒细胞。与人嗜酸性粒细胞共培养的人胎儿肺成纤维细胞-1 细胞中α-平滑肌肌动蛋白的表达明显高于对照组。在纤维母细胞向肌纤维母细胞转化过程中，基质金属蛋白酶-2 的表达增强。基质金属蛋白酶抑制剂阻断嗜酸性粒细胞相关的纤维母细胞向肌纤维母细胞转化，并增加成纤维细胞的迁移。接受小鼠嗜酸性粒细胞过继转移的人基质金属蛋白酶-2 转基因小鼠与野生型小鼠相比，表现出炎症增加和气道重塑进展。这项研究表明，嗜酸性粒细胞诱导纤维母细胞向肌纤维母细胞转化、基质金属蛋白酶-2 的分泌、成纤维细胞的加速迁移，并促进基质金属蛋白酶-2 相关的气道重塑。这些发现为支气管哮喘中嗜酸性粒细胞相关的气道重塑提供了一种新的机制途径。
