Metformin reverses established lung fibrosis in a bleomycin model

Sunad Rangarajan, Nathaniel B. Bone, Anna A. Zmijewska, Shaoning Jiang, Dae Won Park, Karen Bernard, Morgan L. Locy, Saranya Ravi, Jessy Deshane, Roslyn B. Mannon, Edward Abraham, Victor Darley-Usmar, Victor J. Thannickal, Jaroslaw W. Zmijewski

Research output: Contribution to journalArticle

46 Citations (Scopus)

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 injury2–4. 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.

Original languageEnglish
Pages (from-to)1-7
Number of pages7
JournalNature Medicine
DOIs
Publication statusAccepted/In press - 2018 Jul 2

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AMP-Activated Protein Kinases
Metformin
Bleomycin
Fibrosis
Lung
Myofibroblasts
Idiopathic Pulmonary Fibrosis
Apoptosis
Repair
Chemical activation
Tissue
Organelle Biogenesis
Pathologic Processes
indium-bleomycin
Metabolism
Energy Metabolism
Theoretical Models
Switches
Pharmacology
Sensors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Rangarajan, S., Bone, N. B., Zmijewska, A. A., Jiang, S., Park, D. W., Bernard, K., ... Zmijewski, J. W. (Accepted/In press). Metformin reverses established lung fibrosis in a bleomycin model. Nature Medicine, 1-7. https://doi.org/10.1038/s41591-018-0087-6

Metformin reverses established lung fibrosis in a bleomycin model. / Rangarajan, Sunad; Bone, Nathaniel B.; Zmijewska, Anna A.; Jiang, Shaoning; Park, Dae Won; Bernard, Karen; Locy, Morgan L.; Ravi, Saranya; Deshane, Jessy; Mannon, Roslyn B.; Abraham, Edward; Darley-Usmar, Victor; Thannickal, Victor J.; Zmijewski, Jaroslaw W.

In: Nature Medicine, 02.07.2018, p. 1-7.

Research output: Contribution to journalArticle

Rangarajan, S, Bone, NB, Zmijewska, AA, Jiang, S, Park, DW, Bernard, K, Locy, ML, Ravi, S, Deshane, J, Mannon, RB, Abraham, E, Darley-Usmar, V, Thannickal, VJ & Zmijewski, JW 2018, 'Metformin reverses established lung fibrosis in a bleomycin model', Nature Medicine, pp. 1-7. https://doi.org/10.1038/s41591-018-0087-6
Rangarajan, Sunad ; Bone, Nathaniel B. ; Zmijewska, Anna A. ; Jiang, Shaoning ; Park, Dae Won ; Bernard, Karen ; Locy, Morgan L. ; Ravi, Saranya ; Deshane, Jessy ; Mannon, Roslyn B. ; Abraham, Edward ; Darley-Usmar, Victor ; Thannickal, Victor J. ; Zmijewski, Jaroslaw W. / Metformin reverses established lung fibrosis in a bleomycin model. In: Nature Medicine. 2018 ; pp. 1-7.
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