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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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).
The authors declare no competing interests.
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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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