Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan.
Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan.
Respir Res. 2018 Jun 26;19(1):127. doi: 10.1186/s12931-018-0831-y.
Pulmonary fibrosis is a progressive and lethal disease characterized by damage to the lung parenchyma with excess extracellular matrix deposition. The involvement of endothelial cells in fibrosis development is unclear.
We isolated pulmonary endothelial cells, using a magnetic-activated cell sorting system, from mice with pulmonary fibrosis induced by intratracheal bleomycin. We characterized endothelial cells isolated at various times in the course of pulmonary fibrosis development.
Inflammatory cell infiltration was observed at 7 days after bleomycin administration, and fibrotic changes with increased collagen content were observed on day 21. Endothelial cells were isolated at these two timepoints. Levels of von Willebrand factor, plasminogen activator inhibitor-1 and matrix metalloproteinase-12 were elevated in lung endothelial cells isolated from bleomycin-treated mice at days 7 and 21. This indicated that intratracheal bleomycin administration induced endothelium injury. Expression of fibrogenic mediators, transforming growth factor (TGF)-β, connective tissue growth factor and platelet-derived growth factor-C was elevated in the cells from bleomycin-treated, compared with untreated, lungs. When endothelial cells were treated with TGF-β, α-smooth muscle actin (SMA) expression and collagen production were increased only in those cells from bleomycin-treated mouse lungs. Thapsigargin-induced prostaglandin I and nitric oxide production, decreased in endothelial cells from bleomycin-treated mouse lungs, compared with controls, was further suppressed by TGF-β.
Bleomycin administration induced functional changes in lung endothelial cells, indicating potential involvement of endothelium in pulmonary fibrogenesis.
肺纤维化是一种进行性和致命性疾病，其特征是肺实质损伤伴有细胞外基质过度沉积。内皮细胞在纤维化发展中的作用尚不清楚。
我们使用磁激活细胞分选系统从博莱霉素诱导的肺纤维化小鼠中分离肺内皮细胞。我们对纤维化发展过程中不同时间点分离的内皮细胞进行了特征描述。
博莱霉素给药后 7 天观察到炎症细胞浸润，第 21 天观察到纤维化改变和胶原含量增加。在这两个时间点分离了内皮细胞。来自博莱霉素处理的小鼠的肺内皮细胞中，血管性血友病因子、纤溶酶原激活物抑制剂-1 和基质金属蛋白酶-12 的水平在第 7 天和第 21 天升高。这表明气管内博莱霉素给药导致内皮细胞损伤。与未处理的肺相比，来自博莱霉素处理的肺的细胞中纤维化介质转化生长因子 (TGF)-β、结缔组织生长因子和血小板衍生生长因子-C 的表达升高。当内皮细胞用 TGF-β处理时，仅来自博莱霉素处理的小鼠肺的细胞中表达α-平滑肌肌动蛋白 (SMA)和胶原蛋白。与对照组相比，博莱霉素处理的小鼠肺内皮细胞中的前列腺素 I 和一氧化氮产生减少，而 TGF-β进一步抑制了这种减少。
博莱霉素给药诱导了肺内皮细胞的功能变化，表明内皮细胞可能参与了肺纤维化的发生。
