Dynamic Regulation of Platelet-Derived Growth Factor Receptor α Expression in Alveolar Fibroblasts during Realveolarization
Dynamic Regulation of Platelet-Derived Growth Factor Receptor α Expression in Alveolar Fibroblasts during Realveolarization
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DOI：
10.1165/rcmb.2012-0030oc
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发表时间：
2012-10-01
影响因子：
6.4
通讯作者：
Perl, Anne-Karina T.
中科院分区：
文献类型：
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作者：
Chen, Leiling;Acciani, Thomas;Perl, Anne-Karina T.
虽然血小板衍生生长因子受体（PDGFR）-α信号在正常肺泡形成过程中的重要性是已知的，但尚不清楚该信号通路是否可以调节成人肺的再血管化。在肺泡发育期间，PDGFR-α表达细胞诱导平滑肌肌动蛋白（α-SMA）并分化为间质肌成纤维细胞。成纤维细胞生长因子（FGF）信号传导调节肺泡化期间的肌成纤维细胞分化，而过氧化物酶体增殖物激活受体（PPAR）-γ激活拮抗肺纤维化中的肌成纤维细胞分化。使用左肺全肺切除术，评估了在代偿性肺生长期间FGF和PPAR-gamma信号传导在肌成纤维细胞从PDGFR-α阳性前体分化中的作用。FGF受体（FGFR）信号传导通过有条件地激活可溶性显性负性FGFR 2转基因来抑制。通过给予罗格列酮激活PPAR-gamma信号传导。使用免疫组织化学、流式细胞术和实时PCR在PDGFR-α-绿色荧光蛋白（GFP）报告小鼠中评估α-SMA和PDGFR-α蛋白表达的变化。免疫组织化学和流式细胞术表明，细胞比例和表达水平的PDGFR-alpha-GFP在肺泡再生过程中动态变化，并在一个子集的PDGFR-alpha-GFP细胞诱导α-SMA的表达。显性阴性FGFR 2的表达和罗格列酮给药抑制PDGFR-α阳性成纤维细胞中α-SMA的诱导和新隔膜的形成。在左叶肺切除术后评估了上皮和间充质信号分子的基因表达的变化，结果表明，抑制FGFR 2信号传导和增加PPAR-gamma信号传导改变了Shh、FGF、Wnt和Bmp 4的表达，这些基因在早期肺发育期间对上皮-间充质串扰也很重要。我们的数据表明，第一次，一个相当的上皮间充质串扰调节成纤维细胞表型在肺泡分隔。
Although the importance of platelet-derived growth factor receptor (PDGFR)-alpha signaling during normal alveogenesis is known, it is unclear whether this signaling pathway can regulate realveolarization in the adult lung. During alveolar development, PDGFR-alpha-expressing cells induce a smooth muscle actin (alpha-SMA) and differentiate to interstitial myofibroblasts. Fibroblast growth factor (FGF) signaling regulates myofibroblast differentiation during alveolarization, whereas peroxisome proliferator-activated receptor (PPAR)-gamma activation antagonizes myofibroblast differentiation in lung fibrosis. Using left lung pneumonectomy, the roles of FGF and PPAR-gamma signaling in differentiation of myofibroblasts from PDGFR-alpha-positive precursors during compensatory lung growth were assessed. FGF receptor (FGFR) signaling was inhibited by conditionally activating a soluble dominant-negative FGFR2 transgene. PPAR-gamma signaling was activated by administration of rosiglitazone. Changes in alpha-SMA and PDGFR-alpha protein expression were assessed in PDGFR-alpha-green fluorescent protein (GFP) reporter mice using immunohistochemistry, flow cytometry, and real-time PCR. Immunohistochemistry and flow cytometry demonstrated that the cell ratio and expression levels of PDGFR-alpha-GFP changed dynamically during alveolar regeneration and that alpha-SMA expression was induced in a subset of PDGFR-alpha-GFP cells. Expression of a dominant-negative FGFR2 and administration of rosiglitazone inhibited induction of alpha-SMA in PDGFR-alpha-positive fibroblasts and formation of new septae. Changes in gene expression of epithelial and mesenchymal signaling molecules were assessed after left lobe pneumonectomy, and results demonstrated that inhibition of FGFR2 signaling and increase in PPAR-gamma signaling altered the expression of Shh, FGF, Wnt, and Bmp4, genes that are also important for epithelial-mesenchymal crosstalk during early lung development. Our data demonstrate for the first time that a comparable epithelial-mesenchymal crosstalk regulates fibroblast phenotypes during alveolar septation.