Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury

Abstract

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.

Store-operated Ca2+ Entry (SOCE) Induced by Protease-activated Receptor-1 Mediates STIM1 Protein Phosphorylation to Inhibit SOCE in Endothelial Cells through AMP-activated Protein Kinase and p38β Mitogen-activated Protein Kinase

“…AICAR is metabolized to 5-aminoimidazole-4-carboxamide ribonucleoside, which mimics all effects of AMP on AMPK systems (23,34). Zhao et al, (35) have shown that AICAR-mediated AMPK activation reduced endotoxininduced acute lung injury in mice. Another study showed that administration of AMPK activator metformin (anti-diabetic drug) increased the survival rate of endotoxemic mice (36).…”

Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing

“…Although metformin has a broad spectrum of effects, inhibition of mitochondrial complex I and activation of 5' adenosine monophosphate-activated protein kinase (AMPK) appear to be major mechanisms of its action (25,26). Recent studies have shown that besides their ability to regulate cellular metabolism (27), metformin and other AMPK activators can decrease the severity of organ injury in acute inflammatory states (28), including LPS-induced liver injury or acute lung injury (29,30). Metformin, berberine or aminoimidazole carboxamide ribonucleotide (AICAR) were all shown to diminish activation of the tolllike receptor 4 (TLR4)/NF-κB signaling cascade, as well as to release of proinflammatory mediators of neutrophils and macrophages, and also to enhance endothelial integrity in vitro and in models for sepsis (31)(32)(33)(34)(35)(36).…”

AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)

“…The AMPK activator, 5-amino-4-imidazole-carboxamideriboside (AICAR), has been demonstrated to reduce the severity of airway inflammation in murine experimental models of asthma and lipopolysaccharide (LPS)-induced acute lung injury [8,9]. Moreover, the AMPK agonist metformin, currently the most widely prescribed oral blood glucoselowering agent, has been reported to decrease the levels of plasma inflammatory indices, such as C-reactive protein (CRP) [10].…”