A new atlas of the cells in the COPD-afflicted lung has been generated, identifying those cells and pathways that may contribute to the reduced lung function and inflammation characteristic of this disease and that could lead to new therapies. Yale School of Medicine researchers found that genes known to be associated with predisposition to COPD were mostly expressed in structural cells of the lung and not infiltrating immune cells, a novel finding that highlights that the heritability of COPD is driven by structural rather than immune cells.
The research was published Jan. 25 in Nature Communications.
Chronic Obstructive Pulmonary Disease, COPD, is the third leading cause of death worldwide. But the underlying biology is not well understood. The disease is typically caused by inhalation of cigarette smoke or other environmental pollutants. Patients often experience cough and difficulty breathing that gets progressively worse, caused by damage to the lung architecture, persistent inflammation, and reduced lung function.
To better understand which cells in the lungs are connected to these structural and functional changes, the research team—led by Maor Sauler, assistant professor of medicine, and John McDonough, an instructor at the Yale School of Medicine, both from the Section of Pulmonary, Critical Care, and Sleep Medicine—used single-cell RNA sequencing, a method that allowed them to measure the gene activity within each individual cell of a tissue sample. Specifically, they used this method to compare lung tissue from patients with and without COPD.
Their analysis generated an atlas of cells that revealed the extent of cellular and molecular changes that characterize the COPD lung and highlighted new roles for specific cells involved in the function of alveoli—the small air sacs that line the lung and exchange carbon dioxide and oxygen.
Their research pointed the authors specifically to a subtype of alveolar epithelial cells, a cell population that lines the inside surface of the alveoli, provides a physical barrier between the body and the outside environment, mediates gas exchange, and maintains the alveoli. This subtype, known as AT2, or alveolar epithelial type II, secretes surfactant and replaces the cells that do gas exchange when they die. The research team found evidence that in COPD tissues, AT2 cells were substantially altered, lost an enzyme responsible for cellular stress tolerance, and were more likely to die.
“This is completely novel,” said McDonough. “We have studied the role of small airways in COPD in the past, but very little is known about the role of alveolar epithelial cells.”
The researchers also found that endothelial cells, which line the blood vessels in the lung, exhibited inflammatory signals in COPD. “When people think about inflammation, they think about circulating immune cells,” said Sauler.” But our findings suggest that endothelial cells in the lung are also key drivers of chronic inflammation in COPD.”
It has long been suspected that endothelial cells are injured by cigarette smoke, but there was no evidence that endothelial cells serve as regulators of inflammation in the human lung. “This is important,” said Sauler. “We knew that there was increased inflammation in the COPD lung, but we did not know it was regulated by the endothelium. This will change our therapeutic approaches.”
“To develop therapies for COPD, we need to understand what exactly happens in the lung,” he added. “This study provides us with the blueprint to identify cell-specific therapies in a condition that currently has no real effective therapies.”
