U.S. and Canadian researchers have identified a signaling pathway that promotes lung and skin scarring.
Although the study involved mice, the team said the pathway is likely involved in the progression of idiopathic pulmonary fibrosis (IPF) in humans as well. Targeting the pathway may be a way to treat IPF and other fibrotic diseases, they added.
Researchers at Massachusetts General Hospital in Boston and University Health Network in Toronto led the study, titled “ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis.” It was published in the journal Nature Medicine.
“Fibrosis is a component of chronic kidney disease, liver cirrhosis and pulmonary fibrosis,” Dr. David Lagares of Massachusetts General Hospital said in a news release. “The pathway we have identified could be a therapeutic target for halting the process and for restoring organ function.” Lagares, who directs the Matrix and Mechanobiology Program at the hospital’s Fibrosis Research Center, was co-corresponding author of the study.
The process of tissue healing requires several types of cells interacting with each other. The cells include fibroblasts, which produce substances that provide structure to new tissue.
When fibroblasts are out of control, they can produce too much of the substances, leading to tissue scaring. Scientists have yet to understand the workings of the cell mechanisms involved in fibroblast activation and scarring, however.
To try to identify substances that contribute to fibrosis, researchers compared the gene activity of patients with IPF, patients with the skin scarring disease systemic sclerosis, and healthy adults. They looked specifically at the gene responsible for producing the protein ephrin-B2.
They discovered more of the protein in people with tissue scarring than in healthy people. This indicated that the gene was more active in people with fibrosis.
In addition, the team found that mice that lacked the ephrin-B2 protein did not develop lung fibrosis.
Experiments in mice showed that when ephrin-B2 and an enzyme known as ADAM10 interacted, fibroblasts would travel to the site of a lung tissue injury to help it heal. This enzyme reduces the protein’s release of a wound-healing substance called sEphrin-B2, promoting scarring.
“Finding that this extracellular portion of ephrin-B2 was cleaved [stripped] from the cell surface and secreted into the airspace following lung injury was totally unexpected,” Lagares said. This “led us to hypothesize that this soluble form of ephrin-B2 may contribute to lung fibrosis,” he said.
Using chemical inhibitors to block ADAM10 activity prevented sEphrin-B2 production, significantly reducing lung fibrosis in mice and preventing their deaths.
Evaluations of lung fibroblasts collected from IPF patients confirmed that the interaction of sEphrin-B2 and ADAM10 also appears in the human form of the disease. In addition, the team found that IPF patients had higher levels of sEphrin-B2 in their lung fluid and blood plasma than healthy people.
Another finding was that preventing sEphrin-B2 and ADAM10 from interacting reduced levels of several fibrosis-associated proteins in fibroblasts collected from IPF patients. This further confirmed the interaction’s role in fibrosis.
“Our identification of the ADAM10-sEphrin-B2 pathway as a promoter of myofibroblast activation gives us a number of attractive therapeutic targets for pulmonary and other fibrotic diseases,” said Dr. Mohit Kapoor, director of arthritis research at University Health Network’s Krembil Research Institute.
The researchers continue to investigate ephrin-B2’s role in fibrosis. They are also looking at antibodies’ potential to block the protein signaling pathway. This could lead to a therapy to prevent fibrosis, they said.
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