梅尔特克
特发性肺纤维化
纤维化
病理
肺
巨噬细胞
生物
肺纤维化
先天免疫系统
肌成纤维细胞
免疫学
癌症研究
发病机制
免疫系统
医学
细胞生物学
信号转导
内科学
体外
受体酪氨酸激酶
生物化学
作者
Christina Morse,Tracy Tabib,John Sembrat,Kristina L. Buschur,Humberto E. Trejo Bittar,Eleanor Valenzi,Yale Jiang,Daniel J. Kass,Kevin F. Gibson,Wei Chen,Ana L. Mora,Panayiotis V. Benos,Mauricio Rojas,Robert Lafyatis
出处
期刊:The European respiratory journal
[European Respiratory Society]
日期:2019-06-20
卷期号:54 (2): 1802441-1802441
被引量:395
标识
DOI:10.1183/13993003.02441-2018
摘要
A comprehensive understanding of the changes in gene expression in cell types involved in idiopathic pulmonary fibrosis (IPF) will shed light on the mechanisms underlying the loss of alveolar epithelial cells and development of honeycomb cysts and fibroblastic foci. We sought to understand changes in IPF lung cell transcriptomes and gain insight into innate immune aspects of pathogenesis. We investigated IPF pathogenesis using single-cell RNA-sequencing of fresh lung explants, comparing human IPF fibrotic lower lobes reflecting late disease, upper lobes reflecting early disease and normal lungs. IPF lower lobes showed increased fibroblasts, and basal, ciliated, goblet and club cells, but decreased alveolar epithelial cells, and marked alterations in inflammatory cells. We found three discrete macrophage subpopulations in normal and fibrotic lungs, one expressing monocyte markers, one highly expressing FABP4 and INHBA (FABP4 hi ), and one highly expressing SPP1 and MERTK (SPP1 hi ). SPP1 hi macrophages in fibrotic lower lobes showed highly upregulated SPP1 and MERTK expression. Low-level local proliferation of SPP1 hi macrophages in normal lungs was strikingly increased in IPF lungs. Co-localisation and causal modelling supported the role for these highly proliferative SPP1 hi macrophages in activation of IPF myofibroblasts in lung fibrosis. These data suggest that SPP1 hi macrophages contribute importantly to lung fibrosis in IPF, and that therapeutic strategies targeting MERTK and macrophage proliferation may show promise for treatment of this disease.
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