Division of Pulmonary & Critical Care Medicine, University of Virginia, Charlottesville, Virginia, USA.
Section of Pulmonary & Critical Care Medicine, University of Chicago, Chicago, Illinois, USA.
BMJ Open Respir Res. 2023 Feb;10(1). doi: 10.1136/bmjresp-2022-001391.
Contribution of central lung tissues to pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unknown.
To ascertain the relationship between cell types of IPF-central and IPF-peripheral lung explants using RNA sequencing (RNA-seq) transcriptome.
Biopsies of paired IPF-central and IPF-peripheral along with non-IPF lungs were selected by reviewing H&E data. Criteria for differentially expressed genes (DEG) were set at false discovery rate <5% and fold change >2. Computational cell composition deconvolution was performed. Signature scores were computed for each cell type.
Comparison of central IPF versus non-IPF identified 1723 DEG (1522 upregulated and 201 downregulated). Sixty-two per cent (938/1522) of the mutually upregulated genes in central IPF genes were also upregulated in peripheral IPF versus non-IPF. Moreover, 85 IPF central-associated genes (CAG) were upregulated in central IPF versus both peripheral IPF and central non-IPF. IPF single-cell RNA-seq analysis revealed the highest CAG signature score in myofibroblasts and significantly correlated with a previously published activated fibroblasts signature (r=0.88, p=1.6×10). CAG signature scores were significantly higher in IPF than in non-IPF myofibroblasts (p=0.013). Network analysis of central-IPF genes identified a module significantly correlated with the deconvoluted proportion of myofibroblasts in central IPF and anti-correlated with inflammation foci trait in peripheral IPF. The module genes were over-represented in idiopathic pulmonary fibrosis signalling pathways.
Gene expression in central IPF lung regions demonstrates active myofibroblast features that contributes to disease progression. Further elucidation of pathological transcriptomic state of cells in the central regions of the IPF lung that are relatively spared from morphological rearrangements may provide insights into molecular changes in the IPF progression.
特发性肺纤维化（IPF）中心肺组织在发病机制中的作用尚不清楚。
通过 RNA 测序（RNA-seq）转录组确定 IPF 中心和 IPF 外周肺组织中细胞类型的关系。
通过回顾 H&E 数据选择配对的 IPF 中心和 IPF 外周以及非 IPF 肺活检。差异表达基因（DEG）的标准设定为假发现率 <5%和倍数变化 >2。进行计算细胞组成反卷积。为每种细胞类型计算特征评分。
与非 IPF 相比，IPF 中心的比较鉴定出 1723 个 DEG（1522 个上调和 201 个下调）。在 IPF 中心与非 IPF 相比上调的 1522 个相互上调基因中，有 62%（938/1522）也在 IPF 外周与非 IPF 相比上调。此外，85 个 IPF 中心相关基因（CAG）在 IPF 中心与外周 IPF 和中心非 IPF 相比均上调。IPF 单细胞 RNA-seq 分析显示，肌成纤维细胞中的 CAG 特征评分最高，与先前发表的激活成纤维细胞特征显著相关（r=0.88，p=1.6×10）。IPF 肌成纤维细胞中的 CAG 特征评分明显高于非 IPF 肌成纤维细胞（p=0.013）。中央 IPF 基因的网络分析发现，一个模块与中央 IPF 中肌成纤维细胞的反卷积比例显著相关，与外周 IPF 中的炎症灶特征呈负相关。该模块基因在特发性肺纤维化信号通路中过度表达。
IPF 肺中央区域的基因表达显示出活跃的肌成纤维细胞特征，这有助于疾病进展。进一步阐明相对不受形态重排影响的 IPF 肺中央区域细胞的病理转录组状态可能为 IPF 进展中的分子变化提供新的见解。
