Contribution of Epithelial-derived Fibroblasts to Bleomycin-induced Lung Fibrosis
Contribution of Epithelial-derived Fibroblasts to Bleomycin-induced Lung Fibrosis
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DOI：
10.1164/rccm.200903-0322oc
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发表时间：
2009-10-01
影响因子：
24.7
通讯作者：
Lawson, William E.
中科院分区：
文献类型：
--
作者：
Tanjore, Harikrishna;Xu, Xiaochuan C.;Lawson, William E.
理由。肺成纤维细胞是导致过度间质胶原和细胞外基质积累的纤维化的关键介质，但它们的起源并不明确。目的：我们旨在阐明肺上皮来源的成纤维细胞通过上皮-间质转化（EMT）在肺内博莱霉素模型中的贡献。方法：从Immortomice培养原代II型肺泡上皮细胞，并将其暴露于转化生长因子-β（1）和表皮生长因子。开发了用β-半乳糖苷酶永久标记肺上皮谱系细胞的细胞命运报告小鼠以研究EMT，并产生了在成纤维细胞相关S100 A4启动子控制下表达绿色荧光蛋白的骨髓嵌合体以检查骨髓来源的成纤维细胞。小鼠腹腔注射博莱霉素（0.08单位）。S100 A4，β-半乳糖苷酶，绿色荧光蛋白，和α-平滑肌actin. Measures和主要结果：在体外，原代II型肺泡上皮细胞进行EMT的表型变化时，暴露于转化生长因子-β（1）和表皮生长因子与损失的前表面活性蛋白C和E-钙粘蛋白和增益的S100 A4和I型前胶原。在体内，使用细胞命运报告小鼠，大约三分之一的S100 A4阳性成纤维细胞来源于博莱霉素给药后2周的肺上皮。根据骨髓嵌合体研究，在同一时间点，五分之一的S100 A4阳性成纤维细胞来源于骨髓。肌成纤维细胞很少来源于EMT或骨髓祖细胞。结论：EMT和骨髓祖细胞都有助于博莱霉素诱导的肺纤维化中S100 A4阳性成纤维细胞。然而，这两种来源都不是肺成肌纤维细胞的主要贡献者。
Rationale. Lung fibroblasts are key mediators of fibrosis resulting in accumulation of excessive interstitial collagen and extracellular matrix, but their origins are not well defined.Objectives: We aimed to elucidate the contribution of lung epithelium-derived fibroblasts via epithelial-mesenchymal transition (EMT) in the intratracheal bleomycin model.Methods: Primary type II alveolar epithelial cells were cultured from Immortomice and exposed to transforming growth factor-beta(1) and epidermal growth factor. Cell fate reporter mice that permanently mark cells of lung epithelial lineage with beta-galactosidase were developed to study EMT, and bone marrow chimeras expressing green fluorescent protein under the control of the fibroblast-associated S100A4promoter were generated to examine bone marrow-derived fibroblasts. Mice were given intratracheal bleomycin (0.08 unit). Immunostaining was performed for S100A4, beta-galactosidase, green fluorescent protein, and a-smooth muscle actin.Measurements and Main Results: In vitro, primary type II alveolar epithelial cells undergo phenotypic changes of EMT when exposed to transforming growth factor-beta(1) and epidermal growth factor with loss of prosurfactant protein C and E-cadherin and gain of S100A4 and type I procollagen. In vivo, using cell fate reporter mice, approximately one-third of S100A4-positive fibroblasts were derived from lung epithelium 2 weeks after bleomycin administration. From bone marrow chimera studies, one-fifth of S100A4-positive fibroblasts were derived from bone marrow at this same time point. Myofibroblasts rarely derived from EMT or bone marrow progenitors.Conclusions: Both EMT and bone marrow progenitors contribute to S100A4-positive fibroblasts in bleomycin-induced lung fibrosis. However, neither origin is a principal contributor to lung myofibro-blasts.