Hedgehog Signaling in Neonatal and Adult Lung
Hedgehog Signaling in Neonatal and Adult Lung
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DOI：
10.1165/rcmb.2012-0347oc
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发表时间：
2013-06-01
影响因子：
6.4
通讯作者：
Munger, John S.
中科院分区：
文献类型：
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作者：
Liu, Li;Kugler, Matthias C.;Munger, John S.
Sonic Hedgehog（Shh）信号在胚胎肺发育过程中是必不可少的，但其在出生后肺发育和成年肺中的作用尚不清楚。使用Gli 1（nlacZ）报告小鼠识别具有活跃Hh信号传导的细胞，我们发现Gli 1（nlacZ）阳性间充质细胞在出生后2周内密集且弥漫存在，此后数量下降。在成年小鼠中，Gli 1（nlacZ）阳性细胞存在于大气道和血管周围，在肺泡隔中稀疏。Hh刺激的细胞主要是成纤维细胞;只有10%的Gli 1（nlacZ）阳性细胞是平滑肌细胞，大多数平滑肌细胞没有Hh信号的激活。为了评估其功能的相关性，我们影响了Hh信号在发育中的出生后肺和成人受伤的肺。在出生后早期肺发育过程中抑制Hh信号传导可导致肺泡腔扩大，但肺泡分隔不减少。博莱霉素损伤后，在成人肺纤维化病变中有丰富的Gli 1（nlacZ）阳性间充质细胞，在保存的肺泡隔中Gli 1（nlacZ）阳性细胞数量增加。用针对所有Hedgehog同种型的抗体抑制Hh信号传导不会减少博来霉素诱导的纤维化，但腺病毒介导的Shh过表达增加了该模型中的胶原蛋白产生。我们的数据提供了强有力的证据表明，Hh信号可以调节肺基质细胞的功能，在两个关键的情况下：正常发育的出生后肺和肺纤维化在成人肺。
Sonic Hedgehog (Shh) signaling is essential during embryonic lung development, but its role in postnatal lung development and adult lung are not known. Using Gli1(nlacZ) reporter mice to identify cells with active Hh signaling, we found that Gli1(nlacZ)-positive mesenchymal cells are densely and diffusely present up to 2 weeks after birth and decline in number thereafter. In adult mice, Gli1(nlacZ)-positive cells are present around large airways and vessels and are sparse in alveolar septa. Hh-stimulated cells are mostly fibroblasts; only 10% of Gli1(nlacZ)-positive cells are smooth muscle cells, and most smooth muscle cells do not have activation of Hh signaling. To assess its functional relevance, we influenced Hh signaling in the developing postnatal lung and adult injured lung. Inhibition of Hh signaling during early postnatal lung development causes airspace enlargement without diminished alveolar septation. After bleomycin injury in the adult lung, there are abundant Gli1(nlacZ)-positive mesenchymal cells in fibrotic lesions and increased numbers of Gli1(nlacZ)-positive cells in preserved alveolar septa. Inhibition of Hh signaling with an antibody against all Hedgehog isoforms does not reduce bleomycin-induced fibrosis, but adenovirus-mediated overexpression of Shh increases collagen production in this model. Our data provide strong evidence that Hh signaling can regulate lung stromal cell function in two critical scenarios: normal development in postnatal lung and lung fibrosis in adult lung.