Metformin appears to be safe and effective in reversing established lung fibrosis by targeting cell metabolism, according to a study published in the journal Nature Medicine. The study is of great significance because at present there is no effective treatment intervention for the disease although several advancements have been made to reveal the pathological mechanisms of persistent fibrosis. Metformin is a widely used agent for non-insulin-dependent diabetes.
Jaroslaw Zmijewski and his associates conducted a study which showed the reversal of lung fibrosis and the underlying cellular mechanisms affected by the drug treatment.
The research focused on AMP-activated protein kinase (AMPK), an enzyme that senses energy state in the cell and regulates metabolism. Zmijewski and colleagues found that AMPK activity was lower in myofibroblast cells within fibrotic regions of human lung tissue from IPF patients. Myofibroblasts deposit extracellular collagen fiber as part of the fibrosis process. These myofibroblasts were metabolically active and were resistant to the programmed cell death called apoptosis, a natural process that removes more than 50 billion damaged or aged cells in adults each day.
Activation of AMPK in myofibroblasts from lungs of humans with IPF, using the drug metformin or another activator called AICAR, led to lower fibrotic activity. AMPK activation also enhanced the production of new mitochondria, the organelles in cells that produce energy, in the myofibroblasts, and it normalized the cells’ sensitivity to apoptosis.
The researchers used a mouse model for lung fibrosis elicited by the anti-cancer drug bleomycin, and found metformin treatment, starting three weeks after lung injury and continuing for five weeks, accelerated the resolution of well-established fibrosis. Such resolution was not apparent in AMPK-knockout mice, showing that the effect of metformin was AMPK-dependent.
“Together, our studies support the concept that AMPK may function as a critical metabolic switch in promoting resolution of established fibrosis by shifting the balance from anabolic to catabolic metabolism,” the researchers wrote. “Additionally, we provide proof-of-concept that activation of AMPK by metformin or other pharmacologic agents that activate these pro-resolution pathways may be a useful therapeutic strategy for progressive fibrotic disorders.”
Pulmonary fibrosis can develop after lung injuries like infections, radiation or chemotherapy, or it can have an unknown cause, as in idiopathic pulmonary fibrosis or IPF. IPF is a progressive, and ultimately fatal, lung disorder.
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