Established Pulmonary Fibrosis Can Be Reversed Using Diabetes Treatment

July 2, 2018

Researchers at the University of Alabama in Birmingham showed -; for the first time -; this established lung damage can be reversed by using a drug treatment that targets cell metabolism.

This new discovery, reported in the journal Nature Medicine is important because, despite significant progress to reveal persistent pathological mechanisms. Pulmonary fibrosis can develop after lung injury such as infection, radiation or chemotherapy, or may have an unknown cause, such as idiopathic pulmonary fibrosis or IPF. IPF is a progressive, and ultimately fatal, lung disorder that affects more than 150,000 patients a year in the United States and more than 5 million worldwide.

In experiments using lung tissue from FPI patients, mouselung fibroblasts, and a mouse model of pulmonary fibrosis, a team led by Jaroslaw Zmijewski, Ph.D., and Victor Thannickal, MD, showed the following: reversal of pulmonary fibrosis and the underlying cellular mechanisms affected by drug therapy.

Zmijewski and Thannickal are, respectively, badociate professor and professor in the Department of Medicine of UAB. Zmijewski serves as research director for the translation program in ARDS. Thannickal holds the Ben Vaughan Branscomb Chair in Respiratory Diseases and is the Director of the UAB Division of Pulmonary Medicine, Allergy and Critical Care.

Interestingly, the drug that accelerates the resolution of pulmonary fibrosis is metformin, which is a widely used agent for non-insulin-dependent diabetes mellitus.

Research is focused on AMP-activated protein kinase (AMPK), an enzyme that detects the state of energy in the cell and regulates metabolism. Zmijewski, Thannickal and his colleagues found that AMPK activity was lower in myofibroblastic cells in the fibrous regions of human lung tissue from patients with FPI. Myofibroblasts deposit extracellular collagen fibers as part of the fibrosis process. These myofibroblasts were metabolically active and resisted programmed cell death called apoptosis, a natural process that daily eliminates more than 50 billion damaged or elderly cells in adults.

Activation of AMPK in myofibroblasts of human lungs with IPF, using the drug metformin or another activator called AICAR, leads to lower fibrotic activity. The activation of AMPK also stimulates the production of new mitochondria, organelles in cells that produce energy in myofibroblasts, and it normalizes the sensitivity of cells to apoptosis.

Using a murine model of pulmonary fibrosis induced by 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 a resolution was not apparent in the AMPK knockout mice, showing that the effect of metformin depended on AMPK

"Together, our studies support the concept that it is the only way to solve the problem. AMPK can function as a critical metabolic switch in promoting fibrosis-based balance of anabolic metabolism to catabolic metabolism, "the researchers wrote." In addition, we provide proof of concept that activation of AMPK by metformin or other pharmacological agents that activate these pro-resolution pathways may be a useful therapeutic strategy for progressive fibrotic disorders. "

Anabolic metabolism accumulates molecules in the cell to from smaller units, while catabolic metabolism tears large molecules into smaller pieces.