Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
J Pathol. 2013 Jun;230(2):205-14. doi: 10.1002/path.4177. Epub 2013 Apr 3.
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 Kitl(Sl)/Kitl(Sl-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.
干细胞因子 (SCF) 及其受体 c-Kit 已被认为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，其确切作用尚不清楚。在这项研究中，研究了 SCF-c-Kit 轴在肺纤维化中的潜在作用。通过气管内滴注博莱霉素 (BLM) 诱导纤维化，导致血浆、支气管肺泡灌洗液 (BALF) 和肺组织中 SCF 水平升高，以及肺成纤维细胞表达增加。这些变化伴随着骨髓源性 c-Kit(+)细胞在肺中的数量增加，骨髓相应减少。重组 SCF 和来自 BLM 处理动物的肺提取物均可诱导骨髓细胞迁移，而 c-Kit 抑制剂可阻断这种迁移。当与成纤维细胞共培养时，迁移细胞促进肌成纤维细胞分化，提示存在旁分泌致病作用。有趣的是，肺成纤维细胞培养物中存在表达功能性 c-Kit 的细胞亚群，从纤维化肺中分离出的细胞亚群明显更大，对 SCF 的诱导反应更强，包括特发性肺纤维化 (IPF) 患者的肺。该 c-Kit(+)亚群为αSMA 阴性，表达较低水平的胶原 I，但 TGFβ 水平明显高于 c-Kit 阴性细胞。通过气管内给予中和抗 SCF 抗体或在体内使用 Kitl(Sl)/Kitl(Sl-d) 突变小鼠来实现 SCF 缺乏，可显著减少肺纤维化。综上所述，BLM 损伤肺中激活了 SCF-c-Kit 通路，通过募集能够促进肺肌成纤维细胞分化的骨髓祖细胞，可能在肺纤维化中发挥直接作用。
