Researchers are urgently trying to find ways to prevent or slow idiopathic pulmonary fibrosis (IPF) and related lung conditions, which can cause worsen shortness of breath, dry cough, and extreme fatigue. Average survival following diagnosis of IPF is just three to five years, and the disease has no cure. A recent study from the U-M Medical School uncovers a pathway used during normal wound healing that has the potential to reverse IPF. Using a mouse model, they simulated IPF by administering bleomycin and confirmed that the resulting lung scarring resolved itself over the span of about six weeks. This suggests that studying fibrosis is challenging as the body can naturally resolve it on its own without the intervention of experimental drugs.
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. 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.
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. Fortier hopes the discovery that this pathway reverses fibrosis leads to exploration of additional brakes on fibrosis. While much work has focused on how to prevent fibrosis, the ultimate goal is to find a way to reverse it. When a patient presents with symptoms of IPF, the scarring is already present, and the Holy Grail is to find a way to reverse it.
Fortier mentioned that there is a lot to learn about how the mouse gets better on its own when it comes to fibrosis. If the molecular mechanisms by which the resolution occurs can be uncovered, new targets for IPF may be discovered. The team found that the deactivation of fibroblasts is controlled by molecular brakes, with MKP1 playing a key role in this process. By genetically eliminating MKP1 in fibroblasts of mice, the team observed that fibrosis continued uncontrolled, highlighting the importance of this brake in the spontaneous resolution of fibrosis. The study also highlighted the fact that the current FDA approved drugs for lung fibrosis are unable to turn off myofibroblasts, indicating the need for further research into alternative pathways.
The study conducted by the team at U-M Medical School provides insights into a potential pathway to reverse IPF, a debilitating lung condition with no cure. By understanding the molecular mechanisms behind fibrosis resolution, new targets for IPF treatment may be identified. The research focused on the role of MKP1 in deactivating fibroblasts and turning off myofibroblasts, which are responsible for forming scar tissue. The findings suggest that targeting MKP1 and related pathways could be a promising approach to reversing fibrosis in patients with IPF. Further studies are needed to explore additional brakes on fibrosis and develop new therapeutic strategies for this challenging condition.
