Decreased AMP-activated protein kinase (AMPK) function and protective effect of metformin in neonatal rat pups exposed to hyperoxia lung injury. Physiol Rep 2020 Sep;8(18):e14587
Date
09/23/2020Pubmed ID
32959498Pubmed Central ID
PMC7507093DOI
10.14814/phy2.14587Scopus ID
2-s2.0-85091470390 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
We investigated the hypothesis that exposure of lungs at the saccular stage of development to hyperoxia leads to persistent growth arrest and dysfunction of 5'AMP-activated protein kinase (AMPK), a key energy sensor in the cell. We exposed neonatal rat pups from postnatal day 1- day 10 (P1-P10) to ≥90% oxygen or control normoxia. Pups were euthanized at P4 or P10 or recovered in normoxia until euthanasia at P21. Half of the pups in each group received AMPK activator, metformin, or saline intraperitoneally from P1 to P10. Lung histology, morphometric analysis, immunofluorescence, and immunoblots were done for changes in lung structure at P10 and P21 and AMPK function at P4, P10, and P21. Phosphorylation of AMPK (p-AMPK) was decreased in lungs at P10 and P21 in hyperoxia-exposed pups. Metformin increased the levels of p-AMPK and PGC-1α, a downstream AMPK target which regulates mitochondrial biogenesis, at P4, P10, and P21 in hyperoxia pups. Lung ATP levels decreased during hyperoxia and were increased by metformin at P10 and P21. Radial alveolar count and alveolar septal tips were decreased and mean linear intercept increased in hyperoxia-exposed pups at P10 and the changes persisted at P21; these were improved by metformin. Lung capillary number was decreased in hyperoxia-exposed pups at P10 and P21 and was restored by metformin. Hyperoxia leads to impaired AMPK function, energy balance and alveolar simplification. The AMPK activator, metformin improves AMPK function and alveolar and vascular growth in this rat pup model of hyperoxia-induced lung injury.
Author List
Yadav A, Rana U, Michalkiewicz T, Teng RJ, Konduri GGAuthors
Girija Ganesh Konduri MD Chief, Professor in the Pediatrics department at Medical College of WisconsinRu-Jeng Teng MD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAntioxidants
Female
Hyperoxia
Hypoglycemic Agents
Lung
Male
Metformin
Organelle Biogenesis
Oxygen
PPAR gamma
Protein Kinases
Rats
Rats, Sprague-Dawley
