Growth factors secreted by bronchial epithelial cells control myofibroblast proliferation: an in vitro co-culture model of airway remodeling in asthma.
Growth factors secreted by bronchial epithelial cells control myofibroblast proliferation: an in vitro co-culture model of airway remodeling in asthma.
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发表时间：
1999-04
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通讯作者：
Shaoli Zhang;H. Smartt;S. Holgate;W. Roche
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作者：
Shaoli Zhang;H. Smartt;S. Holgate;W. Roche
支气管壁的重塑是哮喘发病的主要决定因素。在哮喘中，支气管上皮基底膜下方的肌成纤维细胞数量增加。在反复损伤后的上皮修复过程中，靠近肌成纤维细胞的上皮细胞产生介质是气道重塑的可能机制之一。在这项研究中，我们建立了一个三维共培养系统，其中将来自人支气管壁的肌成纤维细胞保存在胶原凝胶中，并在凝胶表面生长人支气管上皮细胞系16HBE14o-。通过暴露于作为嗜酸性粒细胞阳离子蛋白替代物的聚-L-精氨酸来化学损伤上皮细胞，并检查成纤维细胞的增殖反应。还测试了来自机械损伤的上皮细胞的条件培养基对成纤维细胞增殖的影响。共培养物中的肌成纤维细胞在聚-L-精氨酸诱导的上皮损伤后显示出显着增强的增殖。来自机械损伤的上皮细胞的条件培养基也增加了成纤维细胞的增殖。上皮扰动后，培养上清液中碱性成纤维细胞生长因子、血小板衍生生长因子、IGF-1、转化生长因子-β2 和内皮素-1 水平增加。上皮损伤后，阻断这些生长因子可抑制成纤维细胞增殖 76%。这项研究表明，上皮细胞是气道重塑的重要调节者，通过旁分泌控制支气管肌成纤维细胞响应细胞损伤和修复。
Remodeling of the bronchial wall is a major determinant of morbidity in asthma. An increased number of myofibroblasts beneath the bronchial epithelial basement membrane has been described in asthma. The production of mediators by epithelial cells in close proximity to myofibroblasts during epithelial repair after repeated damage is one of the possible mechanisms for airway remodeling. In this study, we established a three-dimensional co-culture system in which myofibroblasts derived from human bronchial wall were maintained in collagen gels and a human bronchial epithelial cell line, 16HBE14o-, was grown on the surface of the gels. The epithelial cells were chemically injured by exposure to poly-L-arginine as a surrogate for eosinophil granule cationic protein and the proliferative response of the fibroblasts was examined. Conditioned medium from mechanically damaged epithelial cells was also tested for its effect on fibroblast proliferation. Myofibroblasts in the co-cultures showed significantly enhanced proliferation after poly-L-arginine-induced epithelial damage. Conditioned medium from mechanically damaged epithelial cells also increased fibroblast-proliferation. After epithelial perturbation, basic fibroblast growth factor, platelet-derived growth factor, IGF-1, transforming growth factor-beta2, and endothelin-1 levels increased in culture supernatants. Blockade of these growth factors inhibited fibroblast proliferation by 76% after epithelial injury. This study demonstrates that epithelial cells are an important regulator of airway remodeling by means of paracrine control of bronchial myofibroblasts in response to cell damage and repair.