+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

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



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



Molecular Medicine 21(1): 937-950



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.

(PDF emailed within 0-6 h: $19.90)

Accession: 057109921

Download citation: RISBibTeXText

PMID: 26650187

DOI: 10.2119/molmed.2015.00198


Related references

Inhibition of insulin-stimulated glycogen synthesis by 5-aminoimidasole-4-carboxamide-1-beta-d-ribofuranoside-induced adenosine 5'-monophosphate-activated protein kinase activation: interactions with Akt, glycogen synthase kinase 3-3alpha/beta, and glycogen synthase in isolated rat soleus muscle. Endocrinology 147(11): 5170-5177, 2006

Glycogen Synthase Kinase 3b Is a Natural Activator of Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase Kinase 1 (MEKK1). The Journal of Biological Chemistry 278(16): 995-4001, 2003

Glycogen synthase kinase 3 beta is a natural activator of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1). Journal of Biological Chemistry 278(16): 13995-14001, 2003

The alpha-isoform of glycogen synthase kinase-3 from rabbit skeletal muscle is inactivated by p70 S6 kinase or MAP kinase-activated protein kinase-1 in vitro. Febs Letters 338(1): 37-42, 1994

Luteinizing hormone stimulates mammalian target of rapamycin signaling in bovine luteal cells via pathways independent of AKT and mitogen-activated protein kinase: modulation of glycogen synthase kinase 3 and AMP-activated protein kinase. Endocrinology 151(6): 2846-2857, 2010

Mitogen-activated protein kinase kinase kinase 1 protects against nickel-induced acute lung injury. Toxicological Sciences 104(2): 405-411, 2008

Inactivation of glycogen synthase kinase-3 by epidermal growth factor is mediated by mitogen-activated protein kinase/p90 ribosomal protein S6 kinase signaling pathway in NIH/3T3 cells. Journal of Biological Chemistry 270(3): 987-990, 1995

Glycogen synthase kinase-3beta is tyrosine-phosphorylated by mitogen-activated protein kinase kinase 1 in human skin fibroblasts. Journal of Pharmacological Sciences 94(Supplement 1): 125P, 2004

On the role of phosphatidylinositol 3-kinase, protein kinase b/Akt, and glycogen synthase kinase-3β in photodynamic injury of crayfish neurons and glial cells. Journal of Molecular Neuroscience 45(2): 229-235, 2012

Activation of AMP-Activated Protein Kinase by A769662 Ameliorates Sepsis-Induced Acute Lung Injury in Adult Mice. Shock 2018, 2018

Tumor necrosis factor signaling to stress-activated protein kinase /Jun NH2-terminal kinase and p38 Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38. Journal of Biological Chemistry 273(35): 22681-22692, Aug 28, 1998

Expression of p38 mitogen-activated protein kinases, glycogen synthase kinase, c-Jun NH2-terminal kinase, extracellular signal-regulated kinase signaling: Can it be used as molecular markers among trauma-hemorrhagic shock patients?. Journal of Emergencies, Trauma, and Shock 9(4): 131-132, 2016

Phosphorylation of the type-II regulatory subunit of cyclic-AMP-dependent protein kinase by glycogen synthase kinase 3 and glycogen synthase kinase 5. European Journal of Biochemistry 127(3): 473-481, 1982

Phosphorylation of the type ii regulatory subunit of cyclic amp dependent protein kinase ec 2.7.1.37 by glycogen synthase kinase 3 and glycogen synthase kinase 5. European Journal of Biochemistry 127(3): 473-482, 1982

Studies with wortmannin suggest a role for phosphatidylinositol 3-kinase in the activation of glycogen synthase and mitogen-activated protein kinase by insulin in rat adipocytes: comparison of insulin and protein kinase C modulators. Biochemical and Biophysical Research Communications 209(3): 1082-1088, 1995