Scientists at the Baylor College of Medicine, Yale University, and other institutions say they have identified previously unrecognized changes in gene expression and cellular interactions in distinct cell populations in chronic obstructive pulmonary disease (COPD). The findings highlight the complexity and diversity of cellular injury and inflammation in COPD, which could provide a better understanding of the factors and processes involved in the disease.

The study (“Characterization of the COPD alveolar niche using single-cell RNA sequencing”) published in Nature Communications, used single-cell RNA sequencing to analyze gene expression profiles of lung tissue obtained from patients with COPD and from mice exposed to cigarette smoke. The researchers separated all the cells within the lung and measured the gene expression profile of each individual cell. Then, they organized this information in a cell atlas that is available to researchers interested in exploring gene expression in individual cells in lungs with the disease.

“Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, however our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. Here, we analyze single-cell RNA sequencing profiles of explanted lung tissue from subjects with advanced COPD or control lungs, and we validate findings using single-cell RNA sequencing of lungs from mice exposed to 10 months of cigarette smoke, RNA sequencing of isolated human alveolar epithelial cells, functional in vitro models, and in situ hybridization and immunostaining of human lung tissue samples,” write the investigators.

“We identify a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant cellular metabolism and reduced cellular stress tolerance in COPD. Using transcriptomic network analyses, we predict capillary endothelial cells are inflamed in COPD, particularly through increased CXCL-motif chemokine signaling. Finally, we detect a high-metallothionein expressing macrophage subpopulation enriched in advanced COPD.

“Collectively, these findings highlight cell-specific mechanisms involved in the pathobiology of advanced COPD.”

“Our analysis identified novel changes in gene expression and cellular interactions in three distinct cell populations commonly implicated in COPD: epithelial (in the lungs), endothelial (in blood vessels) and macrophage cells (part of the immune system),” said Ivan Rosas, MD, senior author of the study and section chief of pulmonary, critical care and sleep medicine in the department of medicine at Baylor.

The researchers identified a subpopulation of epithelial cells in lungs with COPD that has abnormal expression of genes involved in metabolic, antioxidant and cellular stress responses, when compared to controls.

“This highly innovative translational study is a continuation of a successful long-standing collaboration with Naftali Kaminski, PhD, and colleagues at Yale University, which has led to the description of multiple lung cell atlases in health and disease that are now publicly available,” added Rosas.

“In this study, Maor Sauler, PhD, and John McDonough of Yale University, the corresponding authors, demonstrate that endothelial cells in capillary blood vessels in COPD lungs are inflamed and that a subpopulation of macrophages expressing high levels of metallothioneins, proteins that regulate the balance of certain metals in the body, seems to contribute to the disease.”

Future studies evaluating outcomes of specific alterations identified in this study are expected to provide further insights into mechanisms that contribute to COPD and having a large and accessible data set of COPD cells, such as the cell atlas, is an essential tool to begin developing therapies to target the condition.

The research team is continuing to focus on developing genomic datasets to better understand the pathologic underpinnings of chronic lung disease. They are currently in the process of completing the largest COVID-19 lung fibrosis cell atlas.

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