Metformin reverses established lung fibrosis in a bleomycin model
- Authors
- Rangarajan, Sunad; Bone, Nathaniel B.; Zmijewskal, 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.
- Issue Date
- Aug-2018
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- NATURE MEDICINE, v.24, no.8, pp 1121 - +
- Indexed
- SCI
SCIE
SCOPUS
- Journal Title
- NATURE MEDICINE
- Volume
- 24
- Number
- 8
- Start Page
- 1121
- End Page
- +
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/3275
- DOI
- 10.1038/s41591-018-0087-6
- ISSN
- 1078-8956
1546-170X
- Abstract
- 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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- Appears in
Collections - 2. Clinical Science > Department of Infectious Diseases > 1. Journal Articles
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