title: Volatile anaesthetics reduce neutrophil inflammatory response by interfering with CXC receptor-2 signalling.
abstract: BACKGROUND
  Growing evidence suggests a protective effect of volatile anaesthetics in ischaemia-reperfusion (I/R)-injury, and the accumulation of neutrophils is a crucial event. Pro-inflammatory cytokines carrying the C-X-C-motif including interleukin-8 (IL-8) and CXC-ligand 1 (CXCL1) activate CXC receptor-1 (CXCR1; stimulated by IL-8), CXC receptor-2 (CXCR2; stimulated by IL-8 and CXCL1), or both to induce CD11b-dependent neutrophil transmigration. Inhibition of CXCR1, CXCR2, or both reduces I/R-injury by preventing neutrophil accumulation. We hypothesized that interference with CXCR1/CXCR2 signalling contributes to the well-established beneficial effect of volatile anaesthetics in I/R-injury.
  
  
  METHODS
  Isolated human neutrophils were stimulated with IL-8 or CXCL1 and exposed to volatile anaesthetics (sevoflurane/desflurane). Neutrophil migration was assessed using an adapted Boyden chamber. Expression of CD11b, CXCR1, and CXCR2 was measured by flow cytometry. Blocking antibodies against CXCR1/CXCR2/CD11b and phorbol myristate acetate were used to investigate specific pathways.
  
  
  RESULTS
  Volatile anaesthetics reduced CD11b-dependent neutrophil transmigration induced by IL-8 by >30% and CD11b expression by 18 and 27% with sevoflurane/desflurane, respectively. This effect was independent of CXCR1/CXCR2 expression and CXCR1/CXCR2 endocytosis. Inhibition of CXCR1 signalling did not affect downregulation of CD11b with volatile anaesthetics. Blocking of CXCR2-signalling neutralized effects by volatile anaesthetics on CD11b expression. Specific stimulation of CXCR2 with CXCL1 was sufficient to induce upregulation of CD11b, which was impaired with volatile anaesthetics. No effect of volatile anaesthetics was observed with direct stimulation of protein kinase C located downstream of CXCR1/CXCR2.
  
  
  CONCLUSIONS
  Volatile anaesthetics attenuate neutrophil inflammatory responses elicited by CXC cytokines through interference with CXCR2 signalling. This might contribute to the beneficial effect of volatile anaesthetics in I/R-injury.
authors.affiliation: Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland Institute of Physiology, Zurich Center of Integrative Human Physiology, University of Zurich, Zürich, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Müller-Edenborn
authors.affiliation: Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland Institute of Physiology, Zurich Center of Integrative Human Physiology, University of Zurich, Zürich, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Frick
authors.affiliation: Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland Institute of Physiology, Zurich Center of Integrative Human Physiology, University of Zurich, Zürich, Switzerland Department of Anesthesiology, University of Illinois Hospital & Health Sciences Center, Chicago, IL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Piegeler
authors.affiliation: Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland Institute of Physiology, Zurich Center of Integrative Human Physiology, University of Zurich, Zürich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Schläpfer
authors.affiliation: Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland Institute of Physiology, Zurich Center of Integrative Human Physiology, University of Zurich, Zürich, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Roth-Z'graggen
authors.affiliation: Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Schlicker
authors.affiliation: Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland Institute of Physiology, Zurich Center of Integrative Human Physiology, University of Zurich, Zürich, Switzerland beatrice.beckschimmer@uzh.ch.
authors.forename: B
authors.initials: B
authors.lastname: Beck-Schimmer
mesh_terms: D000328:Adult; D018685:Anesthetics, Inhalation / Q000097:blood / Q000494:pharmacology*; D000077335:Desflurane; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007249:Inflammation / Q000097:blood*; D007530:Isoflurane / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D008297:Male; D008738:Methyl Ethers / Q000097:blood / Q000494:pharmacology; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects*; D023063:Receptors, Interleukin-8B / Q000097:blood / Q000187:drug effects*; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects*; D055815:Young Adult
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D023063:Receptors, Interleukin-8B; D000077149:Sevoflurane; D000077335:Desflurane; D007530:Isoflurane
keywords: anaesthetics, inhalation, desflurane; anaesthetics, inhalation, sevoflurane; receptors, chemoreceptors