期刊
NATURE MEDICINE
卷 24, 期 8, 页码 1121-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-018-0087-6
关键词
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资金
- Neuroscience Molecular Detection and Stereology Core (UAB) [P30 NS047466]
- National Institutes of Health (NIH) [HL107585]
- US Department of Defense [W81XWH-17-1-0577]
- Pulmonary, Allergy and Critical Care Medicine (UAB) Translational Program
- NIH [P01 HL114470, R01 AG046210, HL135399]
- Department of Veterans Affairs Merit Award [I01BX003056]
- UAB Nathan Shock Center [P30 AG 050886]
Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in a number of organs, including the lungs(1). Cellular metabolism regulates tissue repair and remodelling responses to injury (2-4). AMPK is a critical sensor of cellular bioenergetics and controls the switch from anabolic to catabolic metabolisms. 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 mitochondria! 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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