Metformin reverses established lung fibrosis

July 2, 2018, University of Alabama at Birmingham
Jaroslaw Zmijewski and Victor Thannickal. Credit: UAB

Researchers at the University of Alabama at Birmingham have shown—for the first time—that established lung fibrosis can be reversed using a drug treatment that targets cell metabolism.

This novel finding, reported in the journal Nature Medicine, is important because, despite significant advances to reveal the pathological mechanisms of persistent , effective treatment interventions are lacking.

Pulmonary fibrosis can develop after injuries like infections, radiation or chemotherapy, or it can have an unknown cause, as in , or IPF. IPF is a progressive, and ultimately fatal, that strikes more than 150,000 patients a year in the United States and more than 5 million worldwide.

In experiments using from patients with IPF, mouselung fibroblasts and a murine model of , a team led by Jaroslaw Zmijewski, Ph.D., and Victor Thannickal, M.D., showed the reversal of lung fibrosis and the underlying cellular mechanisms affected by the .

Zmijewski and Thannickal are, respectively, associate professor and professor in the UAB Department of Medicine. Zmijewski serves as research director for the Translational Program in ARDS. Thannickal holds the Ben Vaughan Branscomb Chair of Medicine in Respiratory Disease and is director of the UAB Division of Pulmonary, Allergy and Critical Care Medicine.

Interestingly, the drug that accelerated the resolution of lung fibrosis is metformin, which is a safe and widely used agent for non-insulin-dependent diabetes.

The research focused on AMP-activated protein kinase (AMPK), an enzyme that senses energy state in the cell and regulates metabolism. Zmijewski, Thannickal 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.

Using a mouse model for lung fibrosis elicited by the anti-cancer drug bleomycin, the research team 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."

Explore further: Metformin combats adipose tissue expansion via AMPK

More information: Sunad Rangarajan et al, Metformin reverses established lung fibrosis in a bleomycin model, Nature Medicine (2018). DOI: 10.1038/s41591-018-0087-6

Related Stories

Metformin combats adipose tissue expansion via AMPK

May 24, 2016
(HealthDay)—AMPK activation by metformin is associated with inhibition of interstitial fibrosis and suppression of transforming growth factor β-1 (TGF-β1), according to a study published online May 13 in Diabetes.

NOX4 implicated in fibrosis

April 11, 2014
Genkyotex, a developer of selective NOX enzyme inhibitors, announced today the publication of data showing that GKT137831, a first in class NOX1 and 4 inhibitor, was able to reverse lung fibrosis associated with aging in ...

Radiation and pulmonary fibrosis

November 16, 2017
Radiation-induced pulmonary fibrosis—tissue scarring that can permanently impair lung function—limits the delivery of therapeutic radiation doses to non-small cell lung cancer.

Blocking the molecular source of idiopathic pulmonary fibrosis

May 8, 2018
Idiopathic pulmonary fibrosis (IPF) is one of the most challenging and frustrating diseases that pulmonologists face.

Vaccine improves fibrosis in mouse model of idiopathic pulmonary fibrosis

April 7, 2016
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease characterized by lung fibrosis and declining lung function. There are currently few effective treatments for IPF, and the median survival following diagnosis ...

Restoring lipid synthesis could reduce lung fibrosis

March 6, 2018
Pulmonary fibrosis, an ongoing process of scarring that leaves patients chronically short of breath, can progress in severity until the only course of treatment is lung transplant. A new study shows that restoring the lipids ...

Recommended for you

Drug targets for Ebola, Dengue, and Zika viruses found in lab study

December 13, 2018
No drugs are currently available to treat Ebola, Dengue, or Zika viruses, which infect millions of people every year and result in severe illness, birth defects, and even death. New research from the Gladstone Institutes ...

Faster test for Ebola shows promising results in field trials

December 13, 2018
A team of researchers with members from the U.S., Senegal and Guinea, in cooperation with Becton, Dickinson and Company (BD), has developed a faster test for the Ebola virus than those currently in use. In their paper published ...

Urbanisation and air travel leading to growing risk of pandemic

December 13, 2018
Increased arrivals by air and urbanisation are the two main factors leading to a growing vulnerability to pandemics in our cities, a University of Sydney research team has found.

Researchers discover new interactions between Ebola virus and human proteins

December 13, 2018
Several new connections have been discovered between the proteins of the Ebola virus and human host cells, a finding that provides insight on ways to prevent the deadly Ebola virus from reproducing and could lead to novel ...

Faecal transplants, 'robotic guts' and the fight against deadly gut bugs

December 13, 2018
A simple compound found in our gut could help to stop dangerous bacteria behind severe, and sometimes fatal, hospital infections.

Taking the virus out of a mosquito's bite

December 12, 2018
They approach with the telltale sign—a high-pitched whine. It's a warning that you are a mosquito's next meal. But that mosquito might carry a virus, and now the virus is in you. Now, with the help of state-of-the-art technology, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.