Qualitative Rather than Quantitative Changes Are Hallmarks of Fibroblasts in Bleomycin-Induced Pulmonary Fibrosis
Qualitative Rather than Quantitative Changes Are Hallmarks of Fibroblasts in Bleomycin-Induced Pulmonary Fibrosis
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DOI：
10.1016/j.ajpath.2013.06.005
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发表时间：
2013-09-01
影响因子：
6
通讯作者：
Matsushima, Kouji
中科院分区：
文献类型：
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作者：
Tsukui, Tatsuya;Ueha, Satoshi;Matsushima, Kouji
肺纤维化的特征在于产生过量的细胞外基质组分如I型胶原的活化的成纤维细胞的积累。然而，纤维化过程中成纤维细胞的动力学和活化特征仍然知之甚少，特别是在体内。我们在博莱霉素诱导的肺纤维化模型中检测了急性损伤后肺组织细胞群和活化成纤维细胞表型的变化。尽管在纤维化区域聚集了I型胶原蛋白生成成纤维细胞，但基于流式细胞术的全肺定量分析显示，肺中成纤维细胞的数量保持恒定。在炎症高峰期，成纤维细胞增殖和凋亡均增加，表明成簇不仅是增殖的结果，而且是成纤维细胞从附近肺泡壁迁移的结果。共生实验表明，成纤维细胞不提供从循环。对新鲜分离的成纤维细胞进行的全面基因表达分析揭示了与纤维化相关的详细激活特征，包括负责迁移和细胞外基质构建的基因的变化。编码骨桥蛋白的Spp1基因高度上调，是重塑部位存在的活化成纤维细胞的识别特征。骨桥蛋白可能作为一个有用的标记物的促纤维化成纤维细胞。这些结果提供了深入了解肺纤维化的细胞和分子机制，并为开发特异性抗纤维化疗法提供了基础。
Pulmonary fibrosis is characterized by accumulation of activated fibroblasts that produce excessive amounts of extracellular matrix components such as collagen type I. However, the dynamics and activation signatures of fibroblasts during fibrogenesis remain poorly understood, especially in vivo. We examined changes in lung tissue cell populations and in the phenotype of activated fibroblasts after acute injury in a model of bleomycin-induced pulmonary fibrosis. Despite clustering of collagen type I-producing fibroblasts in fibrotic regions, flow cytometry-based quantitative analysis of whole Lungs revealed that the number of fibroblasts in the lungs remained constant. At the peak of inflammation, fibroblast proliferation and apoptosis were both increased, suggesting that the clustering was not merely a result of proliferation, but also of fibroblast migration from nearby alveolar walls. Parabiosis experiments demonstrated that fibroblasts were not supplied from the circulation. Comprehensive gene expression analysis of freshly isolated fibroblasts revealed a detailed activation signature associated with fibrogenesis, including changes in genes responsible for migration and extracellular matrix construction. The Spp1 gene, which encodes osteopontin, was highly up-regulated and was an identifying characteristic of activated fibroblasts present at the sites of remodeling. Osteopontin may serve as a useful marker of profibrotic fibroblasts. These results provide insights into the cellular and molecular mechanisms underlying pulmonary fibrosis and provide a foundation for development of specific antifibrotic therapies.