Aberrant Multiciliogenesis in Idiopathic Pulmonary Fibrosis.
Aberrant Multiciliogenesis in Idiopathic Pulmonary Fibrosis.
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特发性肺纤维化中的异常多纤毛发生。
DOI：
10.1165/rcmb.2021-0554oc
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发表时间：
2022
影响因子：
6.4
通讯作者：
Burn
中科院分区：
文献类型：
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作者：
Kim,Eunjoo;Mathai,SusanK;Stancil,IanT;Ma,Xiaoqian;Hernandez-Gutierrez,Ashley;Becerra,JessicaN;Marrero-Torres,Emilette;Hennessy,CorinneE;Hatakka,Kristina;Wartchow,EricP;Estrella,Alani;Huber,JonathanP;Cardwell,JonathanH;Burn
我们之前发现了一种新的特发性肺纤维化（IPF）分子亚型，其定义是纤毛相关基因、气道粘蛋白基因MUC5B和基底细胞气道祖细胞的KRT5标记表达增加。在这里，我们展示了人 IPF 气道上皮细胞中 MUC5B 和纤毛基因表达的关联，为检查纤毛基因在 IPF 发病机制中的作用提供了进一步的理论依据。我们证明了 IPF 和博来霉素肺纤维化模型中多纤毛发生的增加和多纤毛细胞活动纤毛结构的变化。重要的是，Krt5 基底细胞中纤毛基因 Ift88（鞭毛内转运 88）的条件删除会减少 Krt5 荚形成和肺纤维化，而俱乐部细胞祖细胞中的 Ift88 条件删除没有观察到任何变化。我们的研究结果表明，异常损伤激活的初级纤毛发生和 Hedgehog 信号传导可能在 Krt5 荚形成中发挥致病作用，从而导致异常的多纤毛发生和肺纤维化。这意味着调节 Krt5 细胞祖细胞中的纤毛基因表达是 IPF 的潜在治疗靶点。
We previously identified a novel molecular subtype of idiopathic pulmonary fibrosis (IPF) defined by increased expression of cilium-associated genes, airway mucin geneMUC5B, andKRT5marker of basal cell airway progenitors. Here we show the association ofMUC5Band cilia gene expression in human IPF airway epithelial cells, providing further rationale for examining the role of cilium genes in the pathogenesis of IPF. We demonstrate increased multiciliogenesis and changes in motile cilia structure of multiciliated cells both in IPF and bleomycin lung fibrosis models. Importantly, conditional deletion of a cilium gene, Ift88 (intraflagellar transport 88), in Krt5 basal cells reduces Krt5 pod formation and lung fibrosis, whereas no changes are observed in Ift88 conditional deletion in club cell progenitors. Our findings indicate that aberrant injury-activated primary ciliogenesis and Hedgehog signaling may play a causative role in Krt5 pod formation, which leads to aberrant multiciliogenesis and lung fibrosis. This implies that modulating cilium gene expression in Krt5 cell progenitors is a potential therapeutic target for IPF.