AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-Induced Lung Injury.

Zhongyu Liu,Jessy Deshane,Shaoning Jiang,Jean-Marc Tadie,Cilina Ann Rodriguez,Nathaniel Bone,Edward Abraham,Jaroslaw W Zmijewski,Dae Won Park,Jean-Francois Pittet

doi:10.2119/molmed.2015.00198

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 bacteria ex 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 eradicate P. aeruginosa in 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.

Highlights

Severe infection accompanied initially by an overly exuberant inflammatory res ponse and later by immunosuppression is frequently associated with dysfunction of vital organs and has a direct impact on morbidity and mortality in critically ill patients [1]
We have shown that the Iκ B kinase beta (IKKβ)/glycogen synthase kinase beta (GSK3β) signaling axis contributes to preventing AMPK activation both after TLR4 engagement in neutrophils and macrophages, and in the lungs of mice subjected to sterile inflammatory conditions, including endotoxemia [38]. it is not known whether this mechanism is operational during polymicrobial interabdominal infection, a clinically relevant issue in sepsis-induced Acute respiratory d istress syndrome (ARDS)
Neutrophils or peritoneal macrophages were incubated with or without the AMPK activator metformin (500 μmol/L), the IKK1/2 inhibitor PS1145 (10 μmol/L) or the GSK3β inhibitor SB216763 (30 μmol/L), and were cultured with P. aeruginosa (PAK; 5 × 107) for 90 min followed by measuring bacterial survival using CFU assays

Summary

Introduction

Severe infection accompanied initially by an overly exuberant inflammatory res ponse and later by immunosuppression is frequently associated with dysfunction of vital organs and has a direct impact on morbidity and mortality in critically ill patients [1]. Sterile inflammatory conditions linked to hemorrhage, trauma or burns worsen organ dysfunction in polymicrobial sepsis [3,4]. Acute respiratory d istress syndrome (ARDS) [5,6] frequently accompanies sepsis, and is associated with higher mortality rates in this setting [7]. Effective pharmacologic interventions are not available for sepsis, a condition that affects more than a million patients each year in the United States [8]. There is no available pharmacologic intervention that improves the outcome from ARDS [9]

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Results

Conclusion