The most common type of pulmonary fibrosis (scarring of the lungs) is idiopathic, meaning it has an unknown cause.
Researchers are urgently trying to find ways to prevent or slow idiopathic pulmonary fibrosis (IPF) and related lung conditions, which can worsen shortness of breath, dry cough, and extreme fatigue. The average survival after diagnosis of IPF is only three to five years and the disease has no cure.
A recent UM study by a team led by Sean Fortier, MD, and Marc Peters-Golden, MD of the Division of Pulmonary and Critical Care Medicine at the UM School of Medicine uncovers a pathway used during normal wound healing. wounds that have the potential to reverse IPF.
Using a mouse model, they simulated IPF by administering bleomycin, a chemotherapy agent that causes cell damage, and confirmed that the resulting lung scars resolved on their own within about six weeks.
Because of this, “studying fibrosis is a little difficult,” Fortier said. “If we are going to give experimental drugs to try to resolve fibrosis, we have to do it before it resolves on its own.
“Otherwise, we won’t be able to know if the resolution was the action of the drug or the body’s natural repair mechanisms.”
However, he said, “there is actually a lot to learn about how the mouse improves on its own. If we can learn the molecular mechanisms by which this occurs, we may discover new targets for IPF.”
The process by which lung injury leads to healing or fibrosis depends in part on what happens to a cell called a fibroblast, which forms connective tissue.
During injury or disease, fibroblasts are activated and become myofibroblasts that form scar tissue by secreting collagen. Once the job is done, these fibroblasts must be deactivated or dedifferentiated to return to their calm state or undergo programmed cell death and be eliminated.
“This is the main distinction between normal wound healing and fibrosis: the persistence of activated myofibroblasts,” Fortier explained. This deactivation is controlled by molecular brakes. The study examined one of these brakes, called MKP1, which the team found was expressed at lower levels in fibroblasts from IPF patients.
By genetically deleting MKP1 in mouse fibroblasts after establishing lung injury, the team saw fibrosis continue unchecked.
“Instead of seeing that good resolution at day 63, you still see fibrosis,” Fortier said.
“We argue by contradiction: when this brake is removed, fibrosis that would otherwise disappear naturally persists, and MKP1 is therefore necessary for the spontaneous resolution of fibrosis.”
They conducted several additional studies using CRISPR techniques to demonstrate how MKP1 applies the brakes, primarily by deactivating the enzyme p38α, involved in a cell’s reaction to stress.
Furthermore, they showed that neither of the two drugs currently approved by the FDA for pulmonary fibrosis, pirfenidone and nintedanib, are able to deactivate myofibroblasts.
“That’s totally consistent with the fact that they slow the progression, but they don’t stop or reverse the disease,” Fortier said.
Fortier hopes that the discovery that this pathway reverses fibrosis will lead to the exploration of additional brakes on fibrosis.
“A lot of work on fibrosis has focused on how we can prevent it, but when a patient comes to my clinic with a dry cough, shortness of breath, and low oxygen levels as a result of underlying IPF, the scars are already present. Of course, “We would love to find a way to stop the scars from getting worse, but the Holy Grail is to reverse it.”