New Atlas of COPD Lung Cells May Help Advance Treatments
A team of researchers have created a comprehensive blueprint of cells that are in the lungs of chronic obstructive pulmonary disease (COPD) patients, which helped them identify previously unknown cell subpopulations and changes in gene activity and cellular interactions.
“Our analysis identified novel changes in gene expression [activity] 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),” Ivan Rosas, MD, the study’s senior author from Baylor College of Medicine, said in a university press release.
The data, open to the public through an online cell atlas, are expected to help scientists better understand the molecular and cellular mechanisms behind COPD and potentially develop new therapies.
Analyses leading up to the creation of the cell atlas were reported in a study, “Characterization of the COPD alveolar niche using single-cell RNA sequencing,” published in the journal Nature Communications.
COPD, associated mainly with long-term exposure to irritants such as cigarette smoke, is characterized by excessive airway inflammation, and abnormal repair and remodeling of the lung epithelium — the tissue that lines the airways. This often results in the progressive destruction of the alveoli, the tiny lung air sacs responsible for gas exchange.
While scientists have gained insight about COPD’s underlying mechanisms over the past decades, “detailed knowledge of cell-type-specific mechanisms and the complex interactions among multiple lung cell types in COPD is lacking,” the researchers wrote.
To address this, Rosas and colleagues at Yale University and other U.S. institutions conducted single-cell gene activity analysis of lung samples from 17 patients with advanced COPD undergoing lung transplant and 15 age-matched healthy lung donors (used as controls).
They focused their analysis on three cell types commonly implicated in COPD: epithelial cells, endothelial cells (those lining blood vessels), and alveolar macrophages.
Abnormalities in lung epithelial and endothelial cells have been shown to contribute to abnormal tissue remodeling in COPD. Alveolar macrophages, a type of immune cell that reside in the alveoli, are known to promote the pro-inflammatory state that characterizes COPD.
The findings were then validated in mice exposed to 10 months of cigarette smoke, lab-grown human alveolar epithelial cells, and human lung tissue samples.
The researchers identified a new subpopulation of alveolar epithelial type 2 (AT2) cells — cells involved in lung tissue repair and regeneration — that showed the greatest gene activity differences between COPD patients and controls.
These cells, named AT2B cells, showed lower-than-normal activity in genes involved in metabolic, antioxidant, and cellular stress responses, and higher activity in genes related to oxidative stress, cell death, and pro-inflammatory molecules; all were previously associated with COPD.
Oxidative stress is a type of cellular damage resulting from an imbalance between the production of potentially harmful oxidant molecules and the cells’ ability to clear them with antioxidants.
AT2B cells also showed the greatest number of genes whose genetic alterations have been associated with COPD-related traits, further emphasizing the importance of this cell type in COPD.
In addition, endothelial cells of lung capillaries, the smallest type of blood vessel, from COPD patients showed the greatest differences in gene activity relative to those from controls. Particularly, these cells showed increased activity in genes involved in inflammatory signaling pathways and lower activity in those promoting endothelial repair.
Further analyses showed several differences in cell-cell interactions between people with and without COPD, especially at the level of inflammatory signaling — particularly of a molecule called CXCL12 — derived from capillary endothelial cells. These findings pinpointed capillary endothelial cells “as major contributors to alveolar inflammation in COPD,” the researchers wrote.
Moreover, the team identified a subpopulation of alveolar macrophages that was highly present in COPD patients relative to controls. This subpopulation showed higher-than-normal activity of genes providing instructions to produce small proteins called metallothioneins.
These findings highlight that capillary endothelial cells “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,” said Rosas, who is the section chief of pulmonary, critical care, and sleep medicine at Baylor’s department of medicine.
They also provide “a high-resolution single-cell atlas of the alveolar niche in the COPD lung” that highlights “the complexity and diversity of cellular injury and inflammation in COPD,” the researchers wrote.
Rosas added: “This highly innovative translational study is a continuation of a successful long-standing collaboration with Dr. Naftali Kaminski 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.”
Future research analyzing the outcomes of specific gene activity changes identified in this study “will provide insights into mechanisms that contribute to disease,” the researchers wrote.