Pulmonary fibrosis (PF) is a form of chronic lung disease characterized by pathologic epithelial remodeling and accumulation of extracellular matrix (ECM). To comprehensively define the cell types, mechanisms, and mediators driving fibrotic remodeling in lungs with PF, we performed single-cell RNA sequencing of single-cell suspensions from 10 nonfibrotic control and 20 PF lungs. Analysis of 114,396 cells identified 31 distinct cell subsets/states. We report that a remarkable shift in epithelial cell phenotypes occurs in the peripheral lung in PF and identify several previously unrecognized epithelial cell phenotypes, including a KRT5⁻/KRT17⁺ pathologic, ECM-producing epithelial cell population that was highly enriched in PF lungs. Multiple fibroblast subtypes were observed to contribute to ECM expansion in a spatially discrete manner. Together, these data provide high-resolution insights into the complexity and plasticity of the distal lung epithelium in human disease and indicate a diversity of epithelial and mesenchymal cells contribute to pathologic lung fibrosis.

肺纤维化（PF）是一种慢性肺部疾病，其特征是病理性上皮重塑和细胞外基质（ECM）积聚。为了全面定义驱动 PF 肺纤维化重塑的细胞类型、机制和介质，我们对 10 个非纤维化对照肺和 20 个 PF 肺的单细胞悬液进行了单细胞 RNA 测序。对 114,396 个细胞的分析确定了 31 个不同的细胞亚群/状态。我们报告说，PF 的外周肺上皮细胞表型发生了显着的变化，并鉴定了几种以前未被识别的上皮细胞表型，包括在 PF 肺中高度富集的KRT5 ^- / KRT17 ⁺病理性、产生 ECM 的上皮细胞群。观察到多种成纤维细胞亚型以空间离散的方式促进 ECM 扩张。总之，这些数据提供了对人类疾病中远端肺上皮的复杂性和可塑性的高分辨率见解，并表明上皮和间质细胞的多样性导致病理性肺纤维化。