Researchers have identified a molecular pathway that leverages the body’s natural healing processes to potentially reverse idiopathic pulmonary fibrosis.
RT’s Three Key Takeaways
- Researchers found that the molecular brake called MKP1, which is expressed at lower levels in fibroblasts from patients with idiopathic pulmonary fibrosis (IPF), is crucial for deactivating myofibroblasts that form scar tissue. When MKP1 is eliminated, fibrosis persists instead of resolving naturally, indicating that MKP1 is necessary for the spontaneous resolution of fibrosis.
- The study demonstrated that MKP1 helps to deactivate the enzyme p38α, which is involved in the cell’s stress response. This deactivation is essential for turning off myofibroblasts, the cells responsible for creating scar tissue during fibrosis. This pathway offers a potential target for therapeutic intervention to reverse fibrosis.
- The research highlighted that current FDA-approved drugs for lung fibrosis, pirfenidone and nintedanib, do not halt or reverse the disease but only slow its progression. They are unable to deactivate myofibroblasts, which is a critical action needed for potentially reversing fibrosis rather than merely stopping its progression.
A recent study by the University of Michigan has identified a pathway used during normal wound healing that could potentially reverse idiopathic pulmonary fibrosis (IPF).
The study, from a team led by Sean Fortier, MD, and Marc Peters-Golden, MD, of the Division of Pulmonary and Critical Care Medicine at U-M Medical School, was published in the Journal of Clinical Investigation.
Simulating IPF in Mice
Using a mouse model, they simulated IPF by administering bleomycin, a chemotherapy agent that causes cell injury and confirmed that the resulting lung scarring resolved itself over the span of about six weeks.
Because of this, “studying fibrosis is kind of tough,” says Fortier in a release. “If we’re going to give experimental drugs to try and resolve fibrosis, we have to do it before it resolves on its own.
Otherwise, we will not be able to tell if the resolution was the action of the drug or natural repair mechanisms of the body.”
However, he says in a release, “There’s actually a lot to learn about how the mouse gets better on its own. If we can learn the molecular mechanisms by which this occurs, we may uncover new targets for IPF.”
The Role of Fibroblasts in Fibrosis
The process by which lung injury either leads to healing or fibrosis relies in part on what happens to a cell called a fibroblast, which forms connective tissue.
During injury or illness, fibroblasts are activated, becoming myofibroblasts that form scar tissue by secreting collagen. When the job is done, these fibroblasts must be deactivated, or de-differentiated, to go back to their quiet state or undergo programmed cell death and be cleared.
“This is the major distinction between normal wound healing and fibrosis—the persistence of activated myofibroblasts,” says Fortier in a release. That 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 patients with IPF.
Genetic Experiments Reveal Critical Mechanisms
By genetically eliminating MKP1 in fibroblasts of mice after establishing lung injury, the team saw that fibrosis continued uncontrolled.
“Instead of at day 63, seeing that nice resolution, you still see fibrosis,” says Fortier in a release. “We argued by contradiction: When you knock out this brake, fibrosis that would otherwise naturally disappear, persists, and therefore MKP1 is necessary for spontaneous resolution of fibrosis.”
They performed several additional studies using CRISPR techniques to demonstrate how MKP1 applies the brakes, mainly by deactivating the enzyme p38α, which is implicated in a cell’s reaction to stress.
Furthermore, they demonstrated that neither of the two current FDA approved drugs for lung fibrosis, pirfenidone and nintedanib, are able to turn off myofibroblasts.
“That’s totally in keeping with the fact that they do slow the progression, but they don’t halt or reverse disease,” says Fortier in a release.
Looking Forward: The Potential for Reversal
Fortier hopes the discovery that this pathway reverses fibrosis leads to exploration of additional brakes on fibrosis.
“So much work on fibrosis has focused on how we can prevent it, but when a patient presents to my clinic with a dry cough, shortness of breath, and low oxygen as a result of underlying IPF, the scarring is already present. Of course, we’d love a way to prevent the scarring from getting worse, but the Holy Grail is to reverse it,” he says in a release.
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