衰老人肺纤维化改变的分子程序。
Molecular programs of fibrotic change in aging human lung.
机构信息
Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep, University of California, San Francisco, CA, USA.
Lung Biology Laboratory, Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY, USA.
出版信息
Nat Commun. 2021 Nov 2;12(1):6309. doi: 10.1038/s41467-021-26603-2.
Lung fibrosis is increasingly detected with aging and has been associated with poor outcomes in acute lung injury or infection. However, the molecular programs driving this pro-fibrotic evolution are unclear. Here we profile distal lung samples from healthy human donors across the lifespan. Gene expression profiling by bulk RNAseq reveals both increasing cellular senescence and pro-fibrotic pathway activation with age. Quantitation of telomere length shows progressive shortening with age, which is associated with DNA damage foci and cellular senescence. Cell type deconvolution analysis of the RNAseq data indicates a progressive loss of lung epithelial cells and an increasing proportion of fibroblasts with age. Consistent with this pro-fibrotic profile, second harmonic imaging of aged lungs demonstrates increased density of interstitial collagen as well as decreased alveolar expansion and surfactant secretion. In this work, we reveal the transcriptional and structural features of fibrosis and associated functional impairment in normal lung aging.
肺纤维化随着年龄的增长而日益被发现，与急性肺损伤或感染的不良预后有关。然而，驱动这种促纤维化演变的分子程序尚不清楚。在这里，我们对健康人类供体的整个生命周期的远端肺部样本进行了分析。通过 bulk RNAseq 进行的基因表达谱分析显示，随着年龄的增长，细胞衰老和促纤维化途径的激活都在增加。端粒长度的定量显示随着年龄的增长逐渐缩短，这与 DNA 损伤焦点和细胞衰老有关。对 RNAseq 数据的细胞类型去卷积分析表明，随着年龄的增长，肺上皮细胞逐渐减少，成纤维细胞的比例逐渐增加。与这种促纤维化特征一致，对老年肺部的二次谐波成像显示间质胶原密度增加，肺泡扩张和表面活性剂分泌减少。在这项工作中，我们揭示了正常肺老化过程中纤维化的转录和结构特征以及相关的功能障碍。
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