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Metformin reverses established lung fibrosis in a bleomycin model

Nature Medicine volume 24, pages 1121–1127 (2018)Cite this article

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An Author Correction to this article was published on 13 August 2018

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Abstract

Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in a number of organs, including the lungs1. Cellular metabolism regulates tissue repair and remodelling responses to injury2,3,4. AMPK is a critical sensor of cellular bioenergetics and controls the switch from anabolic to catabolic metabolism5. However, the role of AMPK in fibrosis is not well understood. Here, we demonstrate that in humans with idiopathic pulmonary fibrosis (IPF) and in an experimental mouse model of lung fibrosis, AMPK activity is lower in fibrotic regions associated with metabolically active and apoptosis-resistant myofibroblasts. Pharmacological activation of AMPK in myofibroblasts from lungs of humans with IPF display lower fibrotic activity, along with enhanced mitochondrial biogenesis and normalization of sensitivity to apoptosis. In a bleomycin model of lung fibrosis in mice, metformin therapeutically accelerates the resolution of well-established fibrosis in an AMPK-dependent manner. These studies implicate deficient AMPK activation in non-resolving, pathologic fibrotic processes, and support a role for metformin (or other AMPK activators) to reverse established fibrosis by facilitating deactivation and apoptosis of myofibroblasts.

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Fig. 1: Distinct patterns of AMPK activity in lung epithelial cells and myofibroblasts of human individuals with IPF.
Fig. 2: AMPK activation reduces the levels of ECM proteins in TGF-β1-treated fibroblasts.
Fig. 3: Effects of AMPK activation on mitochondrial bioenergetics and TGF-β1-mediated resistance to apoptosis in lung fibroblasts.
Fig. 4: Metformin accelerates resolution of bleomycin-induced lung fibrosis.

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  • 13 August 2018

    In the version of this article originally published, a grant was omitted from the Acknowledgements section. The following sentence should have been included: “R.B.M. was supported by a Department of Veterans Affairs Merit Award (5I01BX003272).” The error has been corrected in the HTML and PDF versions of this article.

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Acknowledgements

The authors thank B. Viollet (INSERM) and G. Shailendra (Henry Ford Health System) for providing AMPK α1/2−/− MEFs and AMPKα1−/− mice. The authors thank Y. Liu (Medicine, UAB) for technical support, and J. Creighton (Anesthesiology, UAB) and the Neuroscience Molecular Detection and Stereology Core P30 NS047466 (UAB) for help with lung tissue samples/processing. This work was supported in part by the National Institutes of Health (NIH, HL107585), the US Department of Defense (W81XWH-17-1-0577) and the Pulmonary, Allergy and Critical Care Medicine (UAB) Translational Program for ARDS grants to J.W.Z. V.J.T. was supported by NIH grants P01 HL114470 and R01 AG046210, and a Department of Veterans Affairs Merit Award I01BX003056. Su.R. was supported by NIH K08 (HL135399). V.D.-U. received support from UAB Nathan Shock Center (P30 AG 050886). R.B.M. was supported by a Department of Veterans Affairs Merit Award (5I01BX003272).

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Author notes

  1. These authors contributed equally: Victor J. Thannickal, Jaroslaw W. Zmijewski.

Authors and Affiliations

  1. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Sunad Rangarajan, Nathaniel B. Bone, Anna A. Zmijewska, Shaoning Jiang, Dae Won Park, Karen Bernard, Morgan L. Locy, Jessy Deshane, Roslyn B. Mannon, Victor J. Thannickal & Jaroslaw W. Zmijewski

  2. Division of Infectious Diseases, Korea University Ansan Hospital, Ansan, South Korea

    Dae Won Park

  3. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    Saranya Ravi & Victor Darley-Usmar

  4. Office of the Dean, School of Medicine, University of Miami, Miami, FL, USA

    Edward Abraham

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Contributions

Conception and design was provided by V.J.T. and J.W.Z. Experiments, data analysis and interpretation were carried out by Su.R., S.J., D.W.P., N.B.B., K.B., J.D., A.A.Z., R.B.M., M.L.L., Sa.R., E.A., V.D.-U., V.J.T. and J.W.Z. Drafting and revision of the manuscript was carried out by Su.R., V.J.T. and J.W.Z.

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Correspondence to Victor J. Thannickal or Jaroslaw W. Zmijewski.

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Rangarajan, S., Bone, N.B., Zmijewska, A.A. et al. Metformin reverses established lung fibrosis in a bleomycin model. Nat Med 24, 1121–1127 (2018). https://doi.org/10.1038/s41591-018-0087-6

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