Oxidative damage and TGF-β differentially induce lung epithelial cell sonic hedgehog and tenascin-C expression: implications for the regulation of lung remodelling in idiopathic interstitial lung disease
Oxidative damage and TGF-β differentially induce lung epithelial cell sonic hedgehog and tenascin-C expression: implications for the regulation of lung remodelling in idiopathic interstitial lung disease
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DOI：
10.1111/j.1365-2613.2010.00743.x
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发表时间：
2011-02-01
影响因子：
3
通讯作者：
Wallace, William A. H.
中科院分区：
文献类型：
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作者：
Fitch, Paul M.;Howie, Sarah E. M.;Wallace, William A. H.
特发性间质性肺疾病(ILDs)以炎症、II型肺泡上皮细胞(AECs)增生和肺重构为特征，常伴有进行性纤维化。目前尚不清楚哪些信号启动了iILD和/或维持了疾病过程。通过对三种类型的iILD(普通型间质性肺炎/UIP、非特异性间质性肺炎/非特异性间质性肺炎/NSIP和隐源性机化性肺炎/COP)的实时RT-PCR和免疫组织化学染色，我们研究了Hedgehog信号(先前与肺损伤和修复相关)是否具有功能，以及与损伤相关的细胞外基质蛋白tenascin-C是否存在于所有三种IILD中激活的II型AEC中。通过组织培养、蛋白质和mRNA检测，我们还确定了与iILD发病相关的两个信号(氧化损伤和转化生长因子-β)如何影响II型AEC细胞系的Sonic Hedgehog(SHH)和tenascin-C的产生。我们报道了SHH途径和Tenascin-C在UIP、NSIP和COP中的表达。在uIP中，Shh信号在未成熟的组织纤维组织部位(成纤维细胞灶)最为活跃。在体外，II型血管内皮细胞能结构性地分泌SHH，但不能分泌Tenascin-C。氧化损伤促进SHH的释放，而转化生长因子-β抑制SHH的释放。转化生长因子-β和氧化损伤均可上调肌腱蛋白-C的mRNA表达，但只有转化生长因子-β才能诱导合成和释放一种不同的蛋白质亚型。Shh信号在三种类型的ILD的II型AEC中都是活跃的，并且所有三种类型的ILD都表达tenascin-C。
P>Idiopathic interstitial lung diseases (iILDs) are characterized by inflammation, hyperplasia of Type-II alveolar epithelial cells (AECs) and lung remodelling often with progressive fibrosis. It remains unclear which signals initiate iILD and/or maintain the disease processes. Using real-time RT-PCR and immunohistochemistry on archival biopsies of three patterns of iILD (usual interstitial pneumonitis/UIP, non-specific interstitial pneumonitis/NSIP and cryptogenic organizing pneumonia/COP) we investigated whether hedgehog signalling (previously associated with lung damage and repair) was functional and whether the damage associated extracellular matrix protein tenascin-C was present in activated Type-II AECs in all three iILDs. Using tissue culture, protein and mRNA detection we also determined how two signals (oxidative damage and TGF-beta) associated with iILD pathogenesis affected Sonic hedgehog (SHH) and tenascin-C production by a Type-II AEC cell line. We report that SHH pathway and tenascin-C mRNA and proteins were found in UIP, NSIP and COP. SHH signalling was most active at sites of immature organizing fibrous tissue (fibroblastic foci) in UIP. In vitro Type-II AECs constitutively secrete SHH but not tenascin-C. Oxidative injury stimulated SHH release whereas TGF-beta inhibited it. TGF-beta and oxidative damage both upregulated tenascin-C mRNA but only TGF-beta induced synthesis and release of a distinct protein isoform. SHH signalling is active in Type-II AECs from three types of ILD and all three express tenascin-C.