Researchers at Vanderbilt University Medical Center and the University of Michigan Medical School have identified, in lab studies, a potential new treatment for idiopathic pulmonary fibrosis (IPF), a progressive, incurable lung disease that is on the rise in the United States.
Their report, published Jan. 8 in the journal Science Translational Medicine, is part of a decade-long collaboration with the Translational Genomics Research Institute (TGen) in Phoenix to improve outcomes for the approximately 50,000 patients diagnosed with IPF each year.
“Patients with IPF suffer from severe cough and progressive shortness of breath. Even today, most will require lung transplant surgery, or they will succumb to their disease,” said Scott McCall, MD, PhD, instructor in Medicine in the Division of Allergy, Pulmonary and Critical Care Medicine at VUMC, and the paper’s first author.
“There is an urgent need for new treatments that improve the lives of IPF patients,” added Jonathan Kropski, MD, associate professor of Medicine at VUMC, and senior author of the paper with Timothy Blackwell, MD, chair of the Department of Internal Medicine at the University of Michigan Medical School.
Blackwell formerly directed VUMC’s Division of Allergy, Pulmonary & Critical Care Medicine. The paper’s co-authors include Nicholas Banovich, PhD, associate professor, and division director of Bioinnovation and Genome Sciences at TGen, part of the City of Hope.
IPF is one of the most common forms of pulmonary fibrosis, an interstitial lung disease characterized by the progressive accumulation of scar tissue (fibrosis) in the epithelial lining of the airways. The disease destroys the alveoli, the tiny air sacs where the exchange of oxygen and carbon dioxide takes place.
While “idiopathic” implies no known cause, the risk of IPF increases with age, smoking history, and other environmental, genetic and viral exposures. The disease also tends to co-occur in patients with gastroesophageal reflux disease, sleep apnea and pulmonary hypertension.
The course of IPF is highly variable. Sometimes the disease progresses rapidly, while in other cases, survival after diagnosis can exceed 10 years. Despite recent advances in treatment, however, life expectancy and quality of life have not improved significantly.
The researchers used advanced techniques, including single-cell RNA sequencing (scRNA-seq), to identify variations in the gene-expression profile associated with pulmonary fibrosis. In 2020, they reported that multiple, previously undescribed types of cells in diseased lungs exhibit increased expression of collagen and other fibrotic components of the extracellular matrix.
“Through the past decade, we have learned a great deal about how the cellular makeup of the lung changes in patients with IPF,” Kropski said. “But we were still left with … can these changes be prevented or reversed?”
The current study may provide an answer. “The most exciting part of this work,” said McCall, “is that it demonstrates a new therapeutic approach with the potential to be disease-modifying for IPF.”
Analysis of scRNA-seq data from patients with IPF and a mouse model of repeated injury to lung epithelium revealed persistent activation of hypoxia-inducible factor (HIF) signaling in fibrosis-associated aberrant (abnormal) epithelial cells.
HIF signaling has an unclear role in the repair and regeneration of lung epithelium after acute injury. This work found that under conditions of chronic or repeated injury, however, persistent activation of HIF signaling is associated with dysfunctional epithelial repair and loss of lung function.
In a mouse model of repetitive epithelial injury, the researchers found that deletion or a deficiency of epithelial-targeted Hif1 and Hif2 genes promoted cellular repair programs and limited fibrosis.
Administration of small-molecule HIF2 inhibitor PT-2385 also reduced fibrosis and the appearance of abnormal epithelial cells and promoted alveolar repair. Similarly, PT-2385 enhanced alveolar cell maturation and prevented the emergence of abnormal cells in human lung organoids, cultured tissue used to study lung function in the laboratory.
“Together, these studies showed that HIF2 activation drives the emergence of aberrant epithelial populations after repetitive injury and that targeted HIF2-inhibition may represent an effective therapeutic strategy to promote functional alveolar repair in IPF and other interstitial lung diseases,” the researchers concluded.
With Kropski and several VUMC colleagues, Banovich and Blackwell lead a major research initiative to uncover the molecular drivers of pulmonary disease.
Last year the National Heart Lung and Blood Institute, part of the National Institutes of Health, awarded three competitive grants totaling more than $22 million to VUMC, the University of Michigan, and TGen to support the effort.
McCall, a former postdoctoral clinical fellow in the Division of Allergy, Pulmonary & Critical Care Medicine, is a Vanderbilt Faculty Research Scholar. Other co-authors currently at VUMC are Taylor Sherrill, MS, Carla Calvi, MS, David Han, Jane Camarata, David Nichols, William Lawson, MD, and Jason Gokey, PhD.
This study was supported by NIH/NHLBI grants R01HL145372, R01HL153246, R01HL175555, P01HL092870, and T32HL094296, the U.S. Department of Veterans Affairs, the Vanderbilt Faculty Research Scholars program, the Pulmonary Fibrosis Foundation, and the Francis Family Foundation.
