A new study has discovered a pathway that is used in the normal process of healing wounds and has the potential to reverse IPF. Idiopathic pulmonary fibrosis (IPF) is the most common type of lung fibrosis, which refers to scarring of the lungs with an unknown cause. Researchers are working diligently to find ways to prevent or slow down IPF and other related lung conditions that can lead to worsening symptoms such as shortness of breath, dry cough, and extreme fatigue. The average survival rate after being diagnosed with IPF is only three to five years, and there is currently no cure for the disease. The recent study conducted by a team led by Sean Fortier, M.D. at the University of Michigan has shed light on this potential pathway for reversing IPF.. and Marc Peters-Golden, M.D. of the Division of Pulmonary and Critical Care Medicine at U-M Medical School has discovered a potential pathway to reverse IPF by studying normal wound healing.
They used a mouse model to simulate IPF with bleomycin, a chemotherapy agent that causes cell injury. They found that the resulting lung scarring resolved itself in about six weeks.
Fortier explained that studying fibrosis is challenging because experimental drugs need to be given before the fibrosis resolves on its own in order to effectively reverse it.However, determining whether the improvement was due to the drug’s effects or the body’s natural healing processes is challenging.” He added, “There is still much to be discovered about how the mouse naturally recovers. If we can understand the specific molecular mechanisms involved, we may identify new targets for IPF treatment.” The process of lung injury either leading to healing or fibrosis depends, in part, on the fate of a type of cell called fibroblast, which produces connective tissue. During injury or sickness, fibroblasts are activated and transform into myofibroblasts, which create scar tissue by releasing collagen.
In order for fibroblasts to return to their inactive state or undergo programmed cell death, they need to be deactivated or de-differentiated.
The difference between normal wound healing and fibrosis lies in the persistence of activated myofibroblasts, as stated by Fortier. The deactivation of these cells is controlled by molecular brakes, with the study focusing on one of these brakes called MKP1. It was discovered that MKP1 was expressed at lower levels in fibroblasts from patients with IPF.
The team found that by genetically removing MKP1 in fibroblasts of mice with lung injury, the fibrosis continued to progress uncontrollably.
Instead, 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,” explained Fortier. 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.
By genetically eliminating MKP1 in fibroblasts of mice after establishing lung injury, the team saw that fibrosis continued uncontrolled.
“Instead of being activated, these fibroblasts must be deactivated, or de-differentiated, to return to their quiet state or undergo programmed cell death and be cleared.
Up to day 63, even with the impressive progress, signs of fibrosis are still present,” Fortier explained.
“We reached the conclusion through a process of elimination: when you remove this inhibitor, the fibrosis that would normally go away continues to persist, indicating that MKP1 is essential for the natural resolution of fibrosis.”
They conducted several additional experiments using CRISPR techniques to illustrate how MKP1 functions to inhibit the enzyme p38α, which is involved in a cell’s response to stress.
In addition, they confirmed that neither of the two currently FDA-approved medications for lung fibrosis, pirfenidoneand nintedanib, are capable of deactivating myofibroblasts.
“This is completely consistent with the fact that they slow down the progression, but they don’t stop or reverse the disease,” Fortier stated.
Fortier is optimistic that the discovery of this pathway reversing fibrosis will lead to further investigation into additional methods of controlling fibrosis.
“So much research on fibrosis has concentrated on how to prevent it, but when a patient comes to my clinic with a dry cough, difficulty breathing, and low oxygen levels due to underlying IPF, the scarring is already there. Naturally, we would love a way to stop the scarring from worsening, but the ultimate goal is to reverse it.
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