Role of IGF-1 pathway in lung fibroblast activation.
Role of IGF-1 pathway in lung fibroblast activation.
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DOI：
10.1186/1465-9921-14-102
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发表时间：
2013-10-08
影响因子：
5.8
通讯作者：
Schnapp LM
中科院分区：
文献类型：
--
作者：
Hung CF;Rohani MG;Lee SS;Chen P;Schnapp LM
IGF-1在肺纤维化和急性肺损伤中升高，其中成纤维细胞活化是一个突出特征。我们之前已经证明，在小鼠肺纤维化模型中，阻断IGF通路可以改善预后并减少纤维化。我们现在扩大了这项研究，以检查IGF途径对可能导致纤维化的肺成纤维细胞行为的影响。我们首先研究了在博来霉素诱导肺损伤后，用IGF-1受体阻断抗体A12处理GFP报告基因上游表达αSMA启动子的小鼠。然后，我们检测了IGF-1单独或与促纤维化细胞因子tgf - β联合对体外肌成纤维细胞活化标志物表达的影响，包括αSMA、胶原α1、1型、胶原α1、III型和tgf - β表达。博莱霉素损伤后，我们发现A12处理小鼠αSMA- gfp +细胞数量减少，αSMA免疫荧光染色证实了这一点。我们发现，当成纤维细胞在坚硬基质上培养时，IGF-1单独或与TGF-β联合不影响αSMA RNA表达、启动子活性或蛋白质水平。IGF-1刺激Col1a1和Col3a1在刚性基质上的表达。相反，在软底物上处理IGF-1导致αSMA基因和蛋白表达上调，以及Col1a1和Col3a1转录本上调。综上所述，在软基质环境下，IGF-1刺激成纤维细胞向肌成纤维细胞分化，并对小鼠肺成纤维细胞αSMA应激纤维组织有适度影响。
IGF-1 is elevated in pulmonary fibrosis and acute lung injury, where fibroblast activation is a prominent feature. We previously demonstrated that blockade of IGF pathway in murine model of lung fibrosis improved outcome and decreased fibrosis. We now expand that study to examine effects of IGF pathway on lung fibroblast behaviors that could contribute to fibrosis. We first examined mice that express αSMA promoter upstream of GFP reporter treated with A12, a blocking antibody to IGF-1 receptor, after bleomycin induced lung injury. We then examined the effect of IGF-1 alone, or in combination with the pro-fibrotic cytokine TGFβ on expression of markers of myofibroblast activation in vitro, including αSMA, collagen α1, type 1, collagen α1, type III, and TGFβ expression. After bleomycin injury, we found decreased number of αSMA-GFP + cells in A12 treated mice, validated by αSMA immunofluorescent staining. We found that IGF-1, alone or in combination with TGF-β, did not affect αSMA RNA expression, promoter activity, or protein levels when fibroblasts were cultured on stiff substrate. IGF-1 stimulated Col1a1 and Col3a1 expression on stiff substrate. In contrast, IGF-1 treatment on soft substrate resulted in upregulation of αSMA gene and protein expression, as well as Col1a1 and Col3a1 transcripts. In conclusion, IGF-1 stimulates differentiation of fibroblasts into a myofibroblast phenotype in a soft matrix environment and has a modest effect on αSMA stress fiber organization in mouse lung fibroblasts.
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