Critical Care Medicine  |   September 2016
Adenosine Receptor Adora2b Plays a Mechanistic Role in the Protective Effect of the Volatile Anesthetic Sevoflurane during Liver Ischemia/Reperfusion
Author Notes
  • From the Department of Anaesthesiology and Intensive Care Medicine, Tübingen University Hospital; Eberhard-Karls University Tübingen, Tübingen, Germany.
  • T.F.G. and D.K. contributed equally to this article and share first authorship.
    T.F.G. and D.K. contributed equally to this article and share first authorship.×
  • Submitted for publication December 9, 2015. Accepted for publication June 8, 2016.
    Submitted for publication December 9, 2015. Accepted for publication June 8, 2016.×
  • Address correspondence to: Dr. Straub: Department of Anaesthesiology and Intensive Care Medicine, Eberhard-Karls University Tübingen, Waldhörnlestr. 22, 72072 Tübingen, Germany. andreas.straub@uni-tuebingen.de. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Basic Science / Cardiovascular Anesthesia / Critical Care / Gastrointestinal and Hepatic Systems / Pharmacology
Critical Care Medicine   |   September 2016
Adenosine Receptor Adora2b Plays a Mechanistic Role in the Protective Effect of the Volatile Anesthetic Sevoflurane during Liver Ischemia/Reperfusion
Anesthesiology 9 2016, Vol.125, 547-560. doi:10.1097/ALN.0000000000001234
Anesthesiology 9 2016, Vol.125, 547-560. doi:10.1097/ALN.0000000000001234
Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.