The causes of idiopathic pulmonary fibrosis remain somewhat unclear, which is often the case for conditions in which treatments struggle to achieve more than a slowed progression. There is evidence for cellular senescence to drive the progression of fibrosis, but most research remains focused on the molecular biochemistry of fibroblasts, the cells responsible for building the collagen deposits characteristic of fibrotic tissue.
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. That deactivation is controlled by molecular brakes. The study examined one of these brakes, called MKP1 – which researchers found was expressed at lower levels in fibroblasts from patients with idiopathic pulmonary fibrosis. By genetically eliminating MKP1 in fibroblasts of mice after establishing lung injury, the researchers saw that fibrosis continued uncontrolled.
“Instead of at day 63, seeing that nice resolution, you still see fibrosis. 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. We demonstrated that neither of the 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.”
