title: Age-Dependent Changes in AMPK Metabolic Pathways in the Lung in a Mouse Model of Hemorrhagic Shock.
abstract: The development of multiple organ failure in patients with hemorrhagic shock is significantly influenced by patient age. Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of energy homeostasis, which coordinates metabolic repair during cellular stress. We investigated whether AMPK-regulated signaling pathways are age-dependent in hemorrhage-induced lung injury and whether AMPK activation by 5-amino-4-imidazole carboxamide riboside (AICAR) affords lung protective effects. Male C57/BL6 young mice (3-5 mo), mature adult mice (9-12 mo), and young AMPKα1 knockout mice (3-5 mo) were subjected to hemorrhagic shock by blood withdrawing, followed by resuscitation with shed blood and lactated Ringer's solution. Plasma proinflammatory cytokines were similarly elevated in C57/BL6 young and mature adult mice after hemorrhagic shock. However, mature adult mice exhibited more severe lung edema and neutrophil infiltration, and higher mitochondrial damage in alveolar epithelial type II cells, than did young mice. No change in autophagy was observed. At molecular analysis, the phosphorylation of the catalytic subunit AMPKα1 was associated with nuclear translocation of peroxisome proliferator-activated receptor γ co-activator-α in young, but not mature, adult mice. Treatment with AICAR ameliorated the disruption of lung architecture in mice of both ages; however, effects in mature adult mice were different than young mice and also involved inhibition of nuclear factor-κB. In young AMPKα1 knockout mice, AICAR failed to improve hypotension and lung neutrophil infiltration. Our data demonstrate that during hemorrhagic shock, AMPK-dependent metabolic repair mechanisms are important for mitigating lung injury. However, these mechanisms are less competent with age.
authors.affiliation: 1 Department of Surgery, University of Cincinnati; and.
authors.forename: Lindsey R
authors.initials: LR
authors.lastname: Klingbeil
authors.affiliation: 1 Department of Surgery, University of Cincinnati; and.
authors.forename: Paul
authors.initials: P
authors.lastname: Kim
authors.affiliation: 2 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Piraino
authors.affiliation: 2 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Michael
authors.initials: M
authors.lastname: O'Connor
authors.affiliation: 2 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hake
authors.affiliation: 2 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Vivian
authors.initials: V
authors.lastname: Wolfe
authors.affiliation: 2 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Basilia
authors.identifier: 0000-0003-0152-700X
authors.initials: B
authors.lastname: Zingarelli
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D056809:Alveolar Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D007022:Hypotension / Q000097:blood / Q000150:complications / Q000201:enzymology / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011654:Pulmonary Edema / Q000150:complications / Q000201:enzymology / Q000473:pathology; D012265:Ribonucleotides / Q000494:pharmacology; D012771:Shock, Hemorrhagic / Q000097:blood / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1; C031143:AICA ribonucleotide
keywords: AICAR; AMPK; autophagy; hemorrhagic shock; mitochondria