Lung fibrosis may be reversed using the widely used anti-diabetes drug metformin, US researchers have shown.
In a proof of concept study, researchers at the University of Alabama showed that well-established lung fibrosis can be reversed by agents that switch the fibrosis metabolic pathway from anabolic to catabolic.
The pathway they investigated in human tissue and animal models centres on AMP-activated protein kinase (AMPK), an enzyme that is a critical sensor of cellular bioenergetics and controls the switch from anabolic to catabolic metabolism.
A team led by Associate Professor Jaroslaw Zmijewski (PhD) and respiratory physician Professor Victor Thannickal found that AMPK activity was lower in myofibroblast cells within fibrotic regions of human lung tissue from patients with idiopathic pulmonary fibrosis.
Myofibroblasts deposit extracellular collagen fibre as part of the fibrosis process. These myofibroblasts were metabolically active and were resistant to the programmed cell death called apoptosis.
The team also showed that activation of AMPK in myofibroblasts from lungs of humans with IPF using metformin led to lower fibrotic activity. AMPK activation also enhanced the production of new mitochondria, in the myofibroblasts, and it normalised the cells’ sensitivity to apoptosis.
Using a mouse model for lung fibrosis elicited by the anti-cancer drug bleomycin, the researchers then showed that 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 write in Nature Medicine.
“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.”
They say their novel findings may have important clinical benefits given that effective treatment interventions for idiopathic pulmonary fibrosis are lacking.