Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice
Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice
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DOI：
10.1038/s41467-018-07768-9
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发表时间：
2018-12-18
影响因子：
16.6
通讯作者：
Schwartz, David A.
中科院分区：
文献类型：
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作者：
Hancock, Laura A.;Hennessy, Corinne E.;Schwartz, David A.
功能获得性MUC 5 B启动子变体rs35705950是发生特发性肺纤维化（IPF）的主要风险因素。在这里，我们表明，在人类中，MUC 5 B，粘蛋白被认为是局限于进行气道，共表达与表面活性蛋白C（SFTPC）在2型肺泡上皮细胞和上皮细胞内衬蜂窝囊肿，表明细胞类型参与肺纤维化在远端空域表达MUC 5 B。在小鼠中，我们证明了支气管肺泡上皮中Muc 5 b浓度与粘膜纤毛清除（MCC）受损以及博来霉素诱导的肺纤维化的程度和持续性有关。我们还确定了粘液溶解剂P-2119在Muc 5 b过表达的情况下恢复MCC和抑制博莱霉素诱导的肺纤维化的能力。我们的研究结果表明，粘膜纤毛功能障碍可能在过表达Muc 5 b的小鼠中的博莱霉素诱导的肺纤维化中发挥致病作用，并且远端空气间隙中的MUC 5 B是IPF患者的潜在治疗靶点。
The gain-of-function MUC5B promoter variant rs35705950 is the dominant risk factor for developing idiopathic pulmonary fibrosis (IPF). Here we show in humans that MUC5B, a mucin thought to be restricted to conducting airways, is co-expressed with surfactant protein C (SFTPC) in type 2 alveolar epithelia and in epithelial cells lining honeycomb cysts, indicating that cell types involved in lung fibrosis in distal airspace express MUC5B. In mice, we demonstrate that Muc5b concentration in bronchoalveolar epithelia is related to impaired mucociliary clearance (MCC) and to the extent and persistence of bleomycin-induced lung fibrosis. We also establish the ability of the mucolytic agent P-2119 to restore MCC and to suppress bleomycin-induced lung fibrosis in the setting of Muc5b overexpression. Our findings suggest that mucociliary dysfunction might play a causative role in bleomycin-induced pulmonary fibrosis in mice overexpressing Muc5b, and that MUC5B in distal air-spaces is a potential therapeutic target in humans with IPF.