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Age-Dependent Changes in AMPK Metabolic Pathways in the Lung in a Mouse Model of Hemorrhagic Shock.
- Source :
-
American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2017 May; Vol. 56 (5), pp. 585-596. - Publication Year :
- 2017
-
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.
- Subjects :
- Alveolar Epithelial Cells metabolism
Alveolar Epithelial Cells pathology
Alveolar Epithelial Cells ultrastructure
Aminoimidazole Carboxamide analogs & derivatives
Aminoimidazole Carboxamide pharmacology
Animals
Autophagy drug effects
Blotting, Western
Bronchoalveolar Lavage Fluid
Cell Nucleus drug effects
Cell Nucleus metabolism
Cytokines blood
Disease Models, Animal
Enzyme Activation drug effects
Hypotension blood
Hypotension complications
Hypotension enzymology
Hypotension pathology
Male
Mice
Mice, Inbred C57BL
Mitochondria metabolism
Mitochondria ultrastructure
NF-kappa B metabolism
Neutrophil Infiltration drug effects
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism
Phosphorylation drug effects
Protein Transport drug effects
Pulmonary Edema complications
Pulmonary Edema enzymology
Pulmonary Edema pathology
Ribonucleotides pharmacology
Shock, Hemorrhagic blood
Shock, Hemorrhagic complications
Sirtuin 1 metabolism
AMP-Activated Protein Kinases metabolism
Aging metabolism
Lung metabolism
Lung pathology
Metabolic Networks and Pathways drug effects
Shock, Hemorrhagic enzymology
Shock, Hemorrhagic pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1535-4989
- Volume :
- 56
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- American journal of respiratory cell and molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 28085510
- Full Text :
- https://doi.org/10.1165/rcmb.2016-0118OC