Role of aberrant WNT signalling in the airway epithelial response to cigarette smoke in chronic obstructive pulmonary disease
Role of aberrant WNT signalling in the airway epithelial response to cigarette smoke in chronic obstructive pulmonary disease
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DOI：
10.1136/thoraxjnl-2012-201667
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发表时间：
2013-08-01
期刊：
影响因子：
10
通讯作者：
Postma, Dirkje S.
中科院分区：
文献类型：
--
作者：
Heijink, Irene H.;de Bruin, Harold G.;Postma, Dirkje S.
背景 WNT 信号传导在肺组织损伤和炎症过程中被激活。我们研究了 WNT 配体、受体（卷曲；FZD）或靶基因的肺上皮表达是否因吸烟和/或慢性阻塞性肺病 (COPD) 失调而失调。方法我们在基线和香烟烟雾提取物 (CSE) 暴露时，在来自 COPD 患者和对照（非）吸烟者的人肺上皮细胞系和原代支气管上皮细胞 (PBEC) 中进行了研究。结果 CSE 显着降低了 WNT-4、 WNT-10B和FZD2增加了16HBE中WNT-5B mRNA的表达，但不影响WNT-4蛋白。吸烟者的 PBEC 中 WNT-4（而非其他 WNT 配体）的 mRNA 表达低于非吸烟者，并且所有组的 PBEC 中 CSE 均下调其表达，但 COPD 患者的 PBEC 中的 mRNA 表达高于对照吸烟者。此外，COPD 患者的 PBEC 显示出比吸烟者和非吸烟者更高的 WNT-4 蛋白表达。外源添加WNT-4显着增加16HBE中CXCL8/IL-8、IL-6、CCL5/RANTES、CCL2/MCP-1和血管内皮生长因子（VEGF）的分泌，但不影响经典WNT靶基因MMP-2、MMP-9、纤连蛋白、β-连环蛋白、Dickkopf和axin-2，并诱导非经典信号分子p38的激活。此外，WNT-4 增强了 CSE 诱导的 IL-8 和 VEGF 上调。 结论 COPD 患者 PBEC 中 WNT-4 mRNA 和蛋白水平高于对照（非）吸烟者，而香烟烟雾下调气道上皮 WNT-4 mRNA，但不下调蛋白表达。由于 WNT-4 进一步增加支气管上皮中 CSE 诱导的促炎细胞因子释放，我们认为较高的上皮 WNT-4 水平与吸烟相结合可能对 COPD 气道炎症的发展产生重要影响。
Background WNT signalling is activated during lung tissue damage and inflammation. We investigated whether lung epithelial expression of WNT ligands, receptors (frizzled; FZD) or target genes is dysregulated on cigarette smoking and/or in chronic obstructive pulmonary disease (COPD).Methods We studied this in human lung epithelial cell lines and primary bronchial epithelial cells (PBEC) from COPD patients and control (non-)smokers, at baseline and on cigarette smoke extract (CSE) exposure.Results CSE significantly decreased WNT-4, WNT-10B and FZD2 and increased WNT-5B mRNA expression in 16HBE, but did not affect WNT-4 protein. The mRNA expression of WNT-4, but not other WNT ligands, was lower in PBEC from smokers than non-smokers and downregulated by CSE in PBEC from all groups, yet higher in PBEC from COPD patients than control smokers. Moreover, PBEC from COPD patients displayed higher WNT-4 protein expression than both smokers and non-smokers. Exogenously added WNT-4 significantly increased CXCL8/IL-8, IL-6, CCL5/RANTES, CCL2/MCP-1 and vascular endothelial growth factor (VEGF) secretion in 16HBE, but did not affect the canonical WNT target genes MMP-2, MMP-9, fibronectin, beta-catenin, Dickkopf and axin-2, and induced activation of the non-canonical signalling molecule p38. Moreover, WNT-4 potentiated the CSE-induced upregulation of IL-8 and VEGF.Conclusions WNT-4 mRNA and protein levels are higher in PBEC from COPD patients than control (non-) smokers, while cigarette smoke downregulates airway epithelial WNT-4 mRNA, but not protein expression. As WNT-4 further increases CSE-induced pro-inflammatory cytokine release in bronchial epithelium, we propose that higher epithelial WNT-4 levels in combination with cigarette smoking may have important implications for the development of airway inflammation in COPD.