Insights gained in the pathology of lung disease through single-cell transcriptomics

The human lung is a relatively quiescent organ in the normal healthy state but contains stem/progenitor cells that contribute to normal tissue maintenance and either repair or remodeling in response to injury and disease. Maintenance or repair lead to proper restoration of functional lung tissue and maintenance of physiological functions, with remodeling resulting in altered structure and function that is typically associated with disease. Knowledge of cell types contributing to lung tissue maintenance and repair/remodeling have largely relied on mouse models of injury-repair and lineage tracing of local progenitors. Therefore, many of the functional alterations underlying remodeling in human lung disease have remained poorly defined. However, the advent of advanced genomics approaches to define the molecular phenotype of lung cells at single-cell resolution has paved the way for rapid advances in our understanding of cell types present within the normal human lung and changes that accompany disease. Here we summarize recent advances in our understanding of disease-related changes in the molecular phenotype of human lung epithelium that have emerged from single-cell transcriptomic studies. We focus attention on emerging concepts of epithelial transitional states that characterize the pathological remodeling that accompanies chronic lung diseases, including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, cystic fibrosis, and asthma. Concepts arising from these studies are actively evolving and require corroborative studies to improve our understanding of disease mechanisms. Whenever possible, we highlight opportunities for providing a unified nomenclature in this rapidly advancing field of research. © 2022 The Pathological Society of Great Britain and Ireland.