Division of Pulmonary Biology, Perinatal Institute, Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Am J Respir Cell Mol Biol. 2012 Oct;47(4):517-27. doi: 10.1165/rcmb.2012-0030OC. Epub 2012 May 31.
Although the importance of platelet-derived growth factor receptor (PDGFR)-α signaling during normal alveogenesis is known, it is unclear whether this signaling pathway can regulate realveolarization in the adult lung. During alveolar development, PDGFR-α-expressing cells induce α smooth muscle actin (α-SMA) and differentiate to interstitial myofibroblasts. Fibroblast growth factor (FGF) signaling regulates myofibroblast differentiation during alveolarization, whereas peroxisome proliferator-activated receptor (PPAR)-γ activation antagonizes myofibroblast differentiation in lung fibrosis. Using left lung pneumonectomy, the roles of FGF and PPAR-γ signaling in differentiation of myofibroblasts from PDGFR-α-positive precursors during compensatory lung growth were assessed. FGF receptor (FGFR) signaling was inhibited by conditionally activating a soluble dominant-negative FGFR2 transgene. PPAR-γ signaling was activated by administration of rosiglitazone. Changes in α-SMA and PDGFR-α protein expression were assessed in PDGFR-α-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-α-GFP changed dynamically during alveolar regeneration and that α-SMA expression was induced in a subset of PDGFR-α-GFP cells. Expression of a dominant-negative FGFR2 and administration of rosiglitazone inhibited induction of α-SMA in PDGFR-α-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-γ 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.
虽然已知血小板衍生生长因子受体 (PDGFR)-α 信号在正常肺泡发生中的重要性，但尚不清楚该信号通路是否可以调节成人肺部的肺泡再吸收。在肺泡发育过程中，表达 PDGFR-α 的细胞诱导α平滑肌肌动蛋白 (α-SMA) 并分化为间质成肌纤维细胞。成纤维细胞生长因子 (FGF) 信号在肺泡发生过程中调节成肌纤维细胞的分化，而过氧化物酶体增殖物激活受体 (PPAR)-γ 的激活拮抗肺纤维化中成肌纤维细胞的分化。通过左肺全切除术，评估 FGF 和 PPAR-γ 信号在代偿性肺生长过程中 PDGFR-α 阳性前体细胞向成肌纤维细胞分化中的作用。通过条件性激活可溶性显性负 FGF 受体 2 转基因来抑制 FGFR 信号。通过给予罗格列酮来激活 PPAR-γ 信号。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，在肺泡再生过程中，PDGFR-α-GFP 细胞的比例和表达水平动态变化，并且在 PDGFR-α-GFP 细胞的亚群中诱导了 α-SMA 的表达。表达显性负 FGFR2 和给予罗格列酮抑制 PDGFR-α 阳性成纤维细胞中 α-SMA 的诱导和新闰盘的形成。评估左肺叶切除术切除后上皮和间充质信号分子的基因表达变化，结果表明 FGFR2 信号的抑制和 PPAR-γ 信号的增加改变了 Shh、FGF、Wnt 和 Bmp4 的表达，这些基因在早期肺发育过程中上皮-间充质相互作用也很重要。我们的数据首次证明，类似的上皮-间充质相互作用调节肺泡分隔过程中成纤维细胞表型。
