A team led by USC researchers has identified a target in lung cells that may lead to new treatments for idiopathic pulmonary fibrosis, a progressive disease that ultimately robs a patient of the ability to breathe.
Pulmonary fibrosis, characterized by scarring of the lung, affects about 128,000 people in the United States, with about 48,000 new cases diagnosed annually, according to the Coalition for Pulmonary Fibrosis. Lung damage caused by the disease can’t be repaired, and treatment has focused on improving quality of life.
The researchers discovered that inhibiting certain proteins blocks the interaction between two cellular pathways thought to contribute to pulmonary fibrosis. The discovery represents a new approach to suppress the disease. The study appeared in the March 2 edition of The Journal of Biological Chemistry, the flagship journal of The American Society for Biochemistry and Molecular Biology.
“There is very little research available about the mechanisms that underlie direct interactions between these cell-signaling pathways, although previous studies have suggested that there is crosstalk between the two,” said Zea Borok, senior author of the study and professor of medicine and biochemistry and molecular biology at the Keck School of Medicine of USC.
“Anti-inflammatory treatments that traditionally have been used for pulmonary fibrosis are uniformly ineffective,” added Borok, co-director of the Will Rogers Institute Pulmonary Research Center at USC. “Our research suggests a new approach to treat a disease that is currently incurable.”
A cell-signaling pathway consists of a series of signals that regulate cell behavior. Studying these pathways and how information is transmitted along them may help shed light on disease origins and therapies.
Using rat lung cells, Borok and her colleagues showed that the Wnt/β-catenin and transforming growth factor-β signaling pathways directly interact with one another. The interaction appears to increase expression of the α-smooth muscle actin protein, a hallmark of a biological process associated with fibrosis formation. The researchers confirmed that the interaction also occurs in human lung cells and found that the interactions are dependent on the CREB-binding protein (CBP).
The researchers suggested using ICG-001, an experimental CBP inhibitor developed by co-author Michael Kahn, a USC provost professor in medicine and pharmacy, to stymie the pathway interaction. They posited that ICG-001, which has been shown to be safe for clinical use in colorectal cancer patients, could be used as treatment for pulmonary fibrosis. The next step is to study its efficacy in fibrosis patients.
“Pulmonary fibrosis is the most common of the interstitial lung diseases, with a fatality rate in line with cancer,” Borok said. “These findings have the potential to provide an alternative treatment for patients afflicted by this debilitating disease.”
Researchers from the Beckman Research Institute at City of Hope collaborated on the project. First author Beiyun Zhou, assistant professor of medicine at the Keck School, performed most of the work for the study during her postdoctoral training in Borok’s laboratory.
Other USC co-authors included Edward Crandall, professor of medicine and chairman of the Department of Medicine at the Keck School; Parviz Minoo, professor of pediatrics at the Keck School; and Cu Nguyen, lab manager at the Keck School.
The study was supported with funds from the Hastings Foundation, the L. K. Whittier Foundation and the National Institutes of Health.