Common Diabetes Medication Reverses Pulmonary Fibrosis in Mouse Model of Disease

A common oral medication for type 2 diabetes called metformin was seen to quickly reverse pulmonary fibrosis in a mouse model of the disease and lessen fibrosis in lung tissue of PF patients, a study reports, adding that similar compounds might have similar benefits.

The research, “Metformin reverses established lung fibrosis in a bleomycin model,” appeared in the journal Nature Medicine.

Lung fibrosis, or scarring, is a result of abnormal repair to tissue injured by infections, autoimmune diseases, occupational and environmental exposure to toxic substances, radiation or chemotherapy. It also can stem from causes unknown, as is the case of idiopathic pulmonary fibrosis (IPF).

Tissue repair is regulated by cellular metabolism, which requires the proper functioning of an enzyme called AMPK (short for adenosine monophosphate (AMP)-activated protein kinase), a key sensor of a cell’s energy state and a metabolic regulator.

To better understand the link between AMPK and PF, researchers with The University of Alabama at Birmingham used lung tissues from IPF patients, mice in a model of lung fibrosis, and mouse lung fibroblasts — cells that produce proteins implicated in wound-healing and fibrosis.

They found AMPK activity to be lower-than-usual in fibrotic regions of lung tissue from the IPF patients, particularly in myofibroblasts — cells that, similar to fibroblasts, release collagen during the development of fibrosis. Lower AMPK activity is associated with metabolically active and apoptosis-resistant myofibroblasts, changes that enhance and promote fibrosis. [Apoptosis refers to “programmed” cell death, as opposed to cell death caused by injury; it is used to rid an organism of cells no longer needed or damaged.]

Compounds that activated AMPK in these tissue myofibroblasts showed lesser fibrosis, better mitochondrial production (a cell’s energy source) and normal sensitivity to apoptosis.

Metformin, a widely used treatment for non-insulin-dependent diabetes, is known from previous studies to have anti-fibrotic effects on multiple organs. Metformin is also an activator of AMPK.

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Activating AMPK with metformin or with another AMPK-activator  — one called Aicar — eased fibrosis and increased the production of mitochondria in IPF patients’ myofibroblasts.

In mice with bleomycin-induced lung injury — probably the most used animal model to study PF — this disease is known to resolve over time. But, “the mechanisms promoting resolution are not well understood,” the researchers wrote.

They tested whether metformin could accelerate fibrosis resolution in the bleomycin-affected mice. These animals were given  metformin starting at three weeks after lung injury and continuing for another five weeks. Results showed faster resolution of well-established fibrosis.

Of note, a group of mice genetically altered not to have the AMPK enzyme did not show this benefit, indicating that metformin and its potential benefits were AMPK-dependent.

“These studies implicate deficient AMPK activation in non-resolving, pathologic fibrotic processes,” 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,” they added.