title: AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-Induced Lung Injury.
abstract: Alterations in metabolic and bioenergetic homeostasis contribute to sepsis-mediated organ injury. However, how AMP-activated protein kinase (AMPK), a major sensor and regulator of energy expenditure and production, affects development of organ injury and loss of innate capacity during polymicrobial sepsis remains unclear. In the present experiments, we found that cross-talk between the AMPK and GSK3β signaling pathways controls chemotaxis and the ability of neutrophils and macrophages to kill bacteriaex vivo. In mice with polymicrobial abdominal sepsis or more severe sepsis induced by the combination of hemorrhage and intraabdominal infection, administration of the AMPK activator metformin or the GSK3β inhibitor SB216763 reduced the severity of acute lung injury (ALI). Improved survival in metformin-treated septic mice was correlated with preservation of mitochondrial complex V (ATP synthase) function and increased amounts of ETC complex III and IV. Although immunosuppression is a consequence of sepsis, metformin effectively increased innate immune capacity to eradicateP. aeruginosain the lungs of septic mice. We also found that AMPK activation diminished accumulation of the immunosuppressive transcriptional factor HIF-1α as well as the development of endotoxin tolerance in LPS-treated macrophages. Furthermore, AMPK-dependent preservation of mitochondrial membrane potential also prevented LPS-mediated dysfunction of neutrophil chemotaxis. These results indicate that AMPK activation reduces the severity of polymicrobial sepsis-induced lung injury and prevents the development of sepsis-associated immunosuppression.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Bone
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Shaoning
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Dae Won
authors.initials: DW
authors.lastname: Park
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Tadie
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Jessy
authors.initials: J
authors.lastname: Deshane
authors.affiliation: Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Cilina Ann
authors.initials: CA
authors.lastname: Rodriguez
authors.affiliation: Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Pittet
authors.affiliation: Office of the Dean, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Jaroslaw W
authors.initials: JW
authors.lastname: Zmijewski