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非经典WNT-5A信号通路损害慢性阻塞性肺疾病的内源性肺修复。

Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD.

作者信息

Baarsma Hoeke A, Skronska-Wasek Wioletta, Mutze Kathrin, Ciolek Florian, Wagner Darcy E, John-Schuster Gerrit, Heinzelmann Katharina, Günther Andreas, Bracke Ken R, Dagouassat Maylis, Boczkowski Jorge, Brusselle Guy G, Smits Ron, Eickelberg Oliver, Yildirim Ali Ö, Königshoff Melanie

机构信息

Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Ludwig Maximilians University Munich, University Hospital Grosshadern, 81377 Munich, Germany.

University of Giessen Lung Center, 35392 Giessen, Germany.

出版信息

J Exp Med. 2017 Jan;214(1):143-163. doi: 10.1084/jem.20160675. Epub 2016 Dec 15.

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined. Reduced WNT-β-catenin signaling is linked to impaired lung repair in COPD; however, the factors responsible for attenuating this pathway remain to be elucidated. Here, we identify a canonical to noncanonical WNT signaling shift contributing to COPD pathogenesis. We demonstrate enhanced expression of noncanonical WNT-5A in two experimental models of COPD and increased posttranslationally modified WNT-5A in human COPD tissue specimens. WNT-5A was increased in primary lung fibroblasts from COPD patients and induced by COPD-related stimuli, such as TGF-β, cigarette smoke (CS), and cellular senescence. Functionally, mature WNT-5A attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation in vitro. Lung-specific WNT-5A overexpression exacerbated airspace enlargement in elastase-induced emphysema in vivo. Accordingly, inhibition of WNT-5A in vivo attenuated lung tissue destruction, improved lung function, and restored expression of β-catenin-driven target genes and alveolar epithelial cell markers in the elastase, as well as in CS-induced models of COPD. We thus identify a novel essential mechanism involved in impaired mesenchymal-epithelial cross talk in COPD pathogenesis, which is amenable to therapy.

摘要

慢性阻塞性肺疾病(COPD)是全球主要的死亡原因之一。COPD的一个主要病理特征是功能性肺泡组织丧失且未得到充分修复(肺气肿),但其潜在机制尚不清楚。WNT-β-连环蛋白信号通路减弱与COPD中肺修复受损有关;然而,导致该信号通路减弱的因素仍有待阐明。在此,我们确定了一种从经典WNT信号向非经典WNT信号的转变,这一转变促成了COPD的发病机制。我们证实在两种COPD实验模型中,非经典WNT-5A的表达增强,并且在人类COPD组织标本中,翻译后修饰的WNT-5A增加。在COPD患者的原代肺成纤维细胞中,WNT-5A增加,并由COPD相关刺激诱导,如转化生长因子-β(TGF-β)、香烟烟雾(CS)和细胞衰老。在功能上,成熟的WNT-5A在体外减弱了经典WNT驱动的肺泡上皮细胞伤口愈合和转分化。肺特异性WNT-5A过表达加剧了弹性蛋白酶诱导的肺气肿体内气腔扩大。因此,在体内抑制WNT-5A可减轻肺组织破坏,改善肺功能,并恢复弹性蛋白酶以及CS诱导的COPD模型中β-连环蛋白驱动的靶基因和肺泡上皮细胞标志物的表达。我们因此确定了一种参与COPD发病机制中间充质-上皮细胞串扰受损的新的关键机制,该机制适合进行治疗。

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