title: Adenosine Receptor Adora2b Plays a Mechanistic Role in the Protective Effect of the Volatile Anesthetic Sevoflurane during Liver Ischemia/Reperfusion.
abstract: Liver ischemia/reperfusion (IR) injury is characterized by hepatic tissue damage and an inflammatory response. This is accompanied by the formation and vascular sequestration of platelet-neutrophil conjugates (PNCs). Signaling through Adora2b adenosine receptors can provide liver protection. Volatile anesthetics may interact with adenosine receptors. This study investigates potential antiinflammatory effects of the volatile anesthetic sevoflurane during liver IR.
  
  
  
  Experiments were performed ex vivo with human blood and in a liver IR model with wild-type, Adora2a, and Adora2b mice. The effect of sevoflurane on platelet activation, PNC formation and sequestration, cytokine release, and liver damage (alanine aminotransferase release) was analyzed using flow cytometry, luminometry, and immunofluorescence. Adenosine receptor expression in liver tissue was analyzed using immunohistochemistry and real-time polymerase chain reaction.
  
  
  
  Ex vivo experiments indicate that sevoflurane inhibits platelet and leukocyte activation (n = 5). During liver IR, sevoflurane (2 Vol%) decreased PNC formation 2.4-fold in wild-type (P < 0.05) but not in Adora2b mice (n ≥ 5). Sevoflurane reduced PNC sequestration 1.9-fold (P < 0.05) and alanine aminotransferase release 3.5-fold (P < 0.05) in wild-type but not in Adora2b mice (n = 5). In Adora2a mice, sevoflurane also inhibited PNC formation and cytokine release. Sevoflurane diminished cytokine release (n ≥ 3) and increased Adora2b transcription and expression in liver tissue of wild-types (n = 4).
  
  
  
  Our experiments highlight antiinflammatory and tissue-protective properties of sevoflurane during liver IR and reveal a mechanistic role of Adora2b in sevoflurane-associated effects. The targeted use of sevoflurane not only as an anesthetic but also to prevent IR damage is a promising approach in the treatment of critically ill patients.
authors.affiliation: From the Department of Anaesthesiology and Intensive Care Medicine, Tübingen University Hospital; Eberhard-Karls University Tübingen, Tübingen, Germany.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Granja
authors.forename: David
authors.initials: D
authors.lastname: Köhler
authors.forename: Jessica
authors.initials: J
authors.lastname: Schad
authors.forename: Claudia Bernardo
authors.initials: CB
authors.lastname: de Oliveira
authors.forename: Franziska
authors.initials: F
authors.lastname: Konrad
authors.forename: Michaela
authors.initials: M
authors.lastname: Hoch-Gutbrod
authors.forename: Ariane
authors.initials: A
authors.lastname: Streienberger
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenberger
authors.forename: Andreas
authors.initials: A
authors.lastname: Straub
mesh_terms: D000328:Adult; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008107:Liver Diseases / Q000517:prevention & control*; D008738:Methyl Ethers / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000517:prevention & control*; D000077149:Sevoflurane; D015398:Signal Transduction
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D043704:Receptor, Adenosine A2B; D000077149:Sevoflurane