Intratracheal cell transfer demonstrates the profibrotic potential of resident fibroblasts in pulmonary fibrosis.
Intratracheal cell transfer demonstrates the profibrotic potential of resident fibroblasts in pulmonary fibrosis.
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气管内细胞转移证明了常驻成纤维细胞在肺纤维化中的促纤维化潜力。
DOI：
10.1016/j.ajpath.2015.07.022
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发表时间：
2015
期刊：
影响因子：
6
通讯作者：
and Kouji Matsushima:
中科院分区：
文献类型：
--
作者：
TatsuyaTsukui;Satoshi Ueha;Shigeyuki Shichino;Yutaka Inagaki;and Kouji Matsushima:
肺纤维化是一种毁灭性的疾病，目前几乎没有有效的治疗方法。活化的成纤维细胞形成称为成纤维细胞灶的上皮下簇，其特征在于过度的胶原沉积。活化成纤维细胞的起源存在争议，需要澄清以了解其致病性。在这里，我们使用一种气管内过继细胞转移方法，发现肺泡壁中的成纤维细胞具有最高的促纤维化潜能。通过使用胶原I（α）2-绿色荧光蛋白和神经/胶质抗原2-DsRed荧光报告小鼠，我们根据表面标记物表达和超微结构特征鉴定肺泡壁中的常驻成纤维细胞和周细胞。在博莱霉素诱导的肺纤维化的早期阶段，活化的成纤维细胞迁移到上皮剥脱的肺泡气隙。通过气管内途径递送到损伤的肺泡中的纯化的常驻成纤维细胞显示出与活化的成纤维细胞相似的活化特征并形成成纤维细胞灶。周细胞和上皮细胞都没有相同的促纤维化潜力。转移的常驻成纤维细胞高度上调促纤维化基因，包括α-平滑肌肌动蛋白，是胶原沉积的重要来源。这些数据提供了对纤维化发生的细胞机制的见解，并显示肺内细胞转移是探索抗肺纤维化的新治疗靶点的有用工具。
Pulmonary fibrosis is a devastating disease for which there are few effective therapies. Activated fibroblasts form subepithelial clusters known as fibroblastic foci, which are characterized by excessive collagen deposition. The origin of activated fibroblasts is controversial and needs to be clarified to understand their pathogenicity. Here, using an intratracheal adoptive cell transfer method, we show that resident fibroblasts in alveolar walls have the highest profibrotic potential. By using collagen I(α)2-green fluorescent protein and neural/glial antigen 2-DsRed fluorescent reporter mice, we identified resident fibroblasts and pericytes in the alveolar walls based on surface marker expression and ultrastructural characteristics. In the early phase of bleomycin-induced pulmonary fibrosis, activated fibroblasts migrated into epithelium-denuded alveolar airspaces. Purified resident fibroblasts delivered into injured alveoli by an intratracheal route showed similar activated signatures as activated fibroblasts and formed fibroblastic foci. Neither pericytes nor epithelial cells had the same profibrotic potential. Transferred resident fibroblasts highly up-regulated profibrotic genes including α-smooth muscle actin and were a significant source of collagen deposition. These data provide insights into the cellular mechanisms of fibrogenesis and show intratracheal cell transfer to be a useful tool for exploring novel therapeutic targets against pulmonary fibrosis.