Essential role of stem cell factor-c-Kit signalling pathway in bleomycin-induced pulmonary fibrosis.
Essential role of stem cell factor-c-Kit signalling pathway in bleomycin-induced pulmonary fibrosis.
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DOI：
10.1002/path.4177
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发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Phan SH
中科院分区：
文献类型：
--
作者：
Ding L;Dolgachev V;Wu Z;Liu T;Nakashima T;Wu Z;Ullenbruch M;Lukacs NW;Chen Z;Phan SH
干细胞因子（SCF）及其受体c-Kit与组织重塑和纤维化有关。弥漫性间质纤维化患者的肺泡成纤维细胞分泌更多的SCF。然而，其确切作用仍不清楚。在这项研究中，检查了SCF-c-Kit轴在肺纤维化中的潜在作用。肺内滴注博莱霉素（BLM）诱导肺纤维化，使血浆、支气管肺泡灌洗液（BALF）和肺组织中SCF水平升高，肺成纤维细胞表达增加。这些变化伴随着肺中骨髓来源的c-Kit+细胞数量增加，骨髓中相应的耗竭。BLM处理的动物的重组SCF和肺提取物均诱导骨髓细胞迁移，这被c-Kit抑制剂阻断。迁移的细胞促进肌成纤维细胞分化时，与成纤维细胞共培养，表明旁分泌致病作用。有趣的是，肺成纤维细胞培养物含有表达功能活性c-Kit的细胞亚群，当从纤维化肺分离时，其对SCF诱导的反应显著更大，包括来自特发性肺纤维化（IPF）患者的那些。该c-Kit+亚群为α SMA阴性，表达较低水平的胶原I，但TGFβ水平显著高于c-Kit阴性细胞。通过用中和性抗SCF抗体进行肠内治疗或通过在体内使用KitlSl/KitlSl-d突变小鼠实现的SCF缺乏导致肺纤维化的显著减少。总之，SCF-c-Kit通路在BLM损伤的肺中被激活，并且可能通过招募能够促进肺肌成纤维细胞分化的骨髓祖细胞而在肺纤维化中发挥直接作用。
Stem cell factor (SCF) and its receptor c-Kit have been implicated in tissue remodelling and fibrosis. Alveolar fibroblasts from patients with diffuse interstitial fibrosis secrete more SCF. However, its precise role remains unclear. In this study the potential role of the SCF–c-Kit axis in pulmonary fibrosis was examined. Fibrosis was induced by intratracheal instillation of bleomycin (BLM), which caused increased SCF levels in plasma, bronchoalveolar lavage fluid (BALF) and lung tissue, as well as increased expression by lung fibroblasts. These changes were accompanied by increased numbers of bone marrow-derived c-Kit+ cells in the lung, with corresponding depletion in bone marrow. Both recombinant SCF and lung extracts from BLM-treated animals induced bone-marrow cell migration, which was blocked by c-Kit inhibitor. The migrated cells promoted myofibroblast differentiation when co-cultured with fibroblasts, suggesting a paracrine pathogenic role. Interestingly, lung fibroblast cultures contained a subpopulation of cells that expressed functionally active c-Kit, which were significantly greater and more responsive to SCF induction when isolated from fibrotic lungs, including those from patients with idiopathic pulmonary fibrosis (IPF). This c-Kit+ subpopulation was αSMA-negative and expressed lower levels of collagen I but significantly higher levels of TGFβ than c-Kit-negative cells. SCF deficiency achieved by intratracheal treatment with neutralizing anti-SCF antibody or by use of KitlSl/KitlSl-d mutant mice in vivo resulted in significant reduction in pulmonary fibrosis. Taken together, the SCF–c-Kit pathway was activated in BLM-injured lung and might play a direct role in pulmonary fibrosis by the recruitment of bone marrow progenitor cells capable of promoting lung myofibroblast differentiation.
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影响因子：
2.6
作者：
Nakamura, Y;Tajima, F;Murawaki, Y
通讯作者：
Murawaki, Y
DOI：
10.1084/jem.174.1.63
发表时间：
1991-07-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ogawa M;Matsuzaki Y;Nishikawa S;Hayashi S;Kunisada T;Sudo T;Kina T;Nakauchi H;Nishikawa S
通讯作者：
Nishikawa S
影响因子：
20.1
作者：
Meloni M;Caporali A;Graiani G;Lagrasta C;Katare R;Van Linthout S;Spillmann F;Campesi I;Madeddu P;Quaini F;Emanueli C
通讯作者：
Emanueli C
影响因子：
6
作者：
Dolgachev, Vladislav A.;Ullenbruch, Matthew R.;Phan, Sem H.
通讯作者：
Phan, Sem H.
影响因子：
--
作者：
El Kossi, M. M.;Haylor, J. L.;El Nahas, A. M.
通讯作者：
El Nahas, A. M.