Adenosine monophosphate-activated protein kinase activation protects against sepsis-induced organ injury and inflammation

Abstract

Background Mortality in sepsis is most often attributed to the development of multiple organ failure. In sepsis, inflammation-mediated endothelial activation, defined as a proinflammatory and procoagulant state of the endothelial cells, has been associated with severity of disease. Thus, the objective of this study was to test the hypothesis that AMPK activation limits inflammation and endothelium activation to protect against organ injury in sepsis. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), which is an AMP analogue, has been used to upregulate activity of AMPK. Compound C is a cell-permeable pyrrazolopyrimidine compound that inhibits AMPK activity. Methods Wild-type mice underwent CLP or Sham surgery. Mice were randomized to vehicle, AICAR, or Compound C. Mouse kidney endothelial cells were used for in vitro experiments. Renal and liver function, were determined by serum Cystatin C, BUN, creatinine, and ALT. Serum cytokines were measured by ELISA. Microvascular injury was determined using Evan’s blue dye and electron microscopy. Immunohistochemistry was used to measure protein levels of p-AMPK, LC3, and ICAM. LC3 levels were used as a measure of autophagosome formation. Results AICAR decreased liver, and kidney injury induced by CLP and minimized cytokine elevation, in vivo and in vitro. CLP increased renal and hepatic phosphorylation of AMPK and autophagic signaling as determined by LC3. Inhibition of AMPK with Compound C prevented CLP-induced autophagy and exacerbated tissue injury. Additionally, CLP led to endothelial injury as determined by electron microscopy and Evan’s blue dye extravasation, and AICAR limited this injury. Furthermore, AICAR limited CLP and LPS induced upregulation of ICAM in vivo and in vitro, and decreased LPS induced neutrophil adhesion in vitro. Conclusion In this model, activation of AMPK was protective and AICAR minimized organ injury by decreasing inflammatory cytokines and endothelial activation. These data suggest that AMPK signaling influences sepsis or LPS induced endothelial activation and organ injury.

Stimulation of Brain AMP-Activated Protein Kinase Attenuates Inflammation and Acute Lung Injury in Sepsis

“…Zhao and coworkers demonstrate that AICAR reduces the proinflammatory activity of neutrophils and decreases the severity of ALI through AMPK activation, linking to cellular responses to metabolic stress (13). Escobar et al demonstrate that activation of AMPK by AICAR ameliorates liver and renal injury in septic mice, which is associated with a decrease in circulating cytokines and tissue inflammation (39). In this study, we provide new evidence of activating the CNS in regulating the systemic responses.…”

Mitochondrial Function in Sepsis

“…However, it is also activated by mild hypoxia which causes release of mitochondrial ROS signals (98). AMPK has been shown to protect against organ failure and inflammation in mouse models of experimental sepsis (99). Therefore, manipulation of AMPK using available drugs might be therapeutic in sepsis.…”

Disease tolerance and immunity in host protection against infection

“…This is not associated with overt modulation of the host pathogen load, suggesting that AMPK activation contributes to the establishment of disease tolerance to sepsis 111 . In further support of this notion, pharmacological AMPK activation in the brain is sufficient per se to confer protection against polymicrobial infections in mice 112 .…”

“…Pharmacological targeting of metabolic stress responses such as the one regulated by AMPK, confers protection against the development of organ dysfunction associated with the pathogenesis of sepsis in mice 111 . This is not associated with overt modulation of the host pathogen load, suggesting that AMPK activation contributes to the establishment of disease tolerance to sepsis 111 .…”