Spaziano Giuseppe, Cappetta Donato, Urbanek Konrad, Piegari Elena, Esposito Grazia, Matteis Maria, Sgambato Manuela, Tartaglione Gioia, Russo Rosa, De Palma Raffaele, Rossi Francesco, De Angelis Antonella, D'Agostino Bruno
Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, 80138 Naples, Italy.
Department of Clinical and Experimental Medicine, Second University of Naples, 80137 Naples, Italy.
Mediators Inflamm. 2016;2016:3917471. doi: 10.1155/2016/3917471. Epub 2016 Dec 20.
Structural changes contribute to airway hyperresponsiveness and airflow obstruction in asthma. Emerging evidence points to the involvement of c-kit cells in lung homeostasis, although their potential role in asthma is unknown. Our aim was to isolate c-kit cells from normal mouse lungs and to test whether these cells can interfere with hallmarks of asthma in an animal model. Adult mouse GFP-tagged c-kit cells, intratracheally delivered in the ovalbumin-induced airway hyperresponsiveness, positively affected airway remodeling and improved airway function. In bronchoalveolar lavage fluid of cell-treated animals, a reduction in the number of inflammatory cells and in IL-4, IL-5, and IL-13 release, along with an increase of IL-10, was observed. In MSC-treated mice, the macrophage polarization to M2-like subset may explain, at least in part, the increment in the level of anti-inflammatory cytokine IL-10. After in vitro stimulation of c-kit cells with proinflammatory cytokines, the indoleamine 2,3-dioxygenase and TGF were upregulated. These data, together with the increased apoptosis of inflammatory cells in vivo, indicate that c-kit cells downregulate immune response in asthma by influencing local environment, possibly by cell-to-cell contact combined to paracrine action. In conclusion, intratracheally administered c-kit cells reduce inflammation, positively modulate airway remodeling, and improve function. These data document previously unrecognized properties of c-kit cells, able to impede pathophysiological features of experimental airway hyperresponsiveness.
结构变化导致哮喘中的气道高反应性和气流阻塞。越来越多的证据表明c-kit细胞参与肺稳态，尽管它们在哮喘中的潜在作用尚不清楚。我们的目的是从正常小鼠肺中分离c-kit细胞，并测试这些细胞是否能在动物模型中干扰哮喘的特征。在卵清蛋白诱导的气道高反应性中经气管内递送成年小鼠绿色荧光蛋白标记的c-kit细胞，对气道重塑有积极影响并改善了气道功能。在细胞处理动物的支气管肺泡灌洗液中，观察到炎症细胞数量减少以及IL-4、IL-5和IL-13释放减少，同时IL-10增加。在间充质干细胞处理的小鼠中，巨噬细胞向M2样亚群的极化可能至少部分解释了抗炎细胞因子IL-10水平的升高。在用促炎细胞因子体外刺激c-kit细胞后，吲哚胺2,3-双加氧酶和转化生长因子被上调。这些数据，连同体内炎症细胞凋亡增加，表明c-kit细胞通过影响局部环境下调哮喘中的免疫反应，可能是通过细胞间接触结合旁分泌作用。总之，经气管内给予c-kit细胞可减轻炎症，积极调节气道重塑并改善功能。这些数据证明了c-kit细胞以前未被认识的特性，能够阻碍实验性气道高反应性的病理生理特征。
