October 03, 2018

Metformin reverses established lung fibrosis in a bleomycin model

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Jaroslaw Zmijewski, Ph.D., associate professor the Department of Medicine and research director for the Translational Program for Acute Respiratory Distress Syndrome (TP-ARDS), is the latest winner of the School of Medicine’s Featured Discovery. This initiative celebrates the important research from School of Medicine faculty members. In experiments using lung tissues from patients with IPF, mouselung fibroblasts and a murine model of lung fibrosis, a team led by Zmijewski showed the reversal of lung fibrosis and the underlying cellular mechanisms affected by the drug treatment. These findings are important because despite significant advances to reveal the pathological mechanisms of persistent fibrosis, effective treatment interventions are lacking. Read more from UAB News here.

The School of Medicine communications staff sat down with Dr. Harrington to gather insights about her research, UAB and the science community. 

RS21326_Jaroslaw Zmijewski -11-scr.jpgQ: What compelled you to pursue this research?

A: In spite of significant advances in understanding mechanisms involved in development of lung injury and lung fibrosis, therapeutic interventions are very limited. The major focus of our lab is to establish whether metabolic “switches” and modulators of mitochondrial function are viable targets to promote of fibrosis resolution. In particular, key questions are related to bioenergetic and metabolic reprogramming of myofibroblast that may impair wound healing followed by persistent scar formation and respiratory dysfunction.

Q: What was your most unexpected finding?

A: The most unexpected and promising finding is that activation of AMP-activated protein kinase (AMPK), major bioenergetic sensor and metabolic regulator, effectively reversed the maladaptive phenotype of lung fibroblasts. This includes dysfunctional autophagy/extracellular matrix (ECM) degradation and acquisition of apoptosis resistance; both events are implicated in accumulation of activated myofibroblasts during persistent fibrosis. These initial results open an exciting possibility to test the effects of metformin, an AMPK activator, in a model of lung fibrosis in mice. We found that metformin therapeutically accelerates the resolution of well-established fibrosis in an AMPK-dependent manner.

Q: How do you feel your research will impact the science community?

A: To our knowledge, this is the first study to demonstrate that the resolution of lung fibrosis can be accelerated with a pharmacological intervention that targets cellular metabolism. We also provided new mechanistic insights to myofibroblast maladaptive reprogramming associated with defective autophagy and ECM turnover, as well as mitochondrial dysfunction linked to myofibroblast resistance to apoptosis.

Q: What is your research’s relevance to human disease?

A: Pulmonary fibrosis can be a result of injurious conditions, including environmental exposure or unknown etiologies associated with idiopathic pulmonary fibrosis (IPF). IPF is a progressive, and ultimately fatal, respiratory disorder that affects more than 150,000 patients annually in the USA, and over 5 million worldwide. Our studies utilized lung fibroblasts from control and IPF lungs and examined IPF lung sections versus normal regions. We have shown that AMPK activation is an important therapeutic and translational target. Further clinical trials should establish the efficacy of AMPK activators, including potential benefit of metformin in IPF.

Q: What do you find makes the science community here unique?

A: Our unique research environment helps me and others to integrate interdisciplinary research projects, acquire grants and provide mentorship opportunities. In particular, I appreciate a highly collaborative effort that merges basic research with clinically relevant issues. As an example, our discovery is possible only because of comprehensive collaboration with Dr. Victor J. Thannickal (PACCM) and Dr. Victor Darley-Usmar (Pathology)—leading experts in lung fibrosis and mitochondrial bioenergetics, respectively.

View the publication online.

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