Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury.
AMP-activated protein kinase (AMPK) is activated by increases in the intracellular AMP-to-ATP ratio and plays a central role in cellular responses to metabolic stress. Although activation of AMPK has been shown to have anti-inflammatory effects, there is little information concerning the role that AMPK may play in modulating neutrophil function and neutrophil-dependent inflammatory events, such as acute lung injury. To examine these issues, we determined the effects of pharmacological activators of AMPK, 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) and barberine, on Toll-like receptor 4 (TLR4)-induced neutrophil activation. AICAR and barberine dose-dependently activated AMPK in murine bone marrow neutrophils. Exposure of LPS-stimulated neutrophils to AICAR or barberine inhibited release of TNF-alpha and IL-6, as well as degradation of IkappaBalpha and nuclear translocation of NF-kappaB, compared with findings in neutrophil cultures that contained LPS without AICAR or barberine. Administration of AICAR to mice resulted in activation of AMPK in the lungs and was associated with decreased severity of LPS-induced lung injury, as determined by diminished neutrophil accumulation in the lungs, reduced interstitial pulmonary edema, and diminished levels of TNF-alpha and IL-6 in bronchoalveolar lavage fluid. These results suggest that AMPK activation reduces TLR4-induced neutrophil activation and diminishes the severity of neutrophil-driven proinflammatory processes, including acute lung injury.
Zhao
Xia
X
Dept. of Medicine, Univ. of Alabama at Birmingham School of Medicine, BDB 420, 1530 3rd Ave. S, Birmingham, AL 35294-0012, USA.
Zmijewski
Jaroslaw W
JW
Lorne
Emmanuel
E
Liu
Gang
G
Park
Young-Jun
YJ
Tsuruta
Yuko
Y
Abraham
Edward
E
D000208:Acute Disease; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D007249:Inflammation / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000503:physiopathology*; D055370:Lung Injury; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D012265:Ribonucleotides / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000502:physiology
D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012265:Ribonucleotides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000620:Aminoimidazole Carboxamide; D017868:Cyclic AMP-Dependent Protein Kinases; C031143:AICA ribonucleotide