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ANESTHETIC PHARMACOLOGY

Molecular Evidence of Late Preconditioning After Sevoflurane Inhalation in Healthy Volunteers

Eliana Lucchinetti, PhD^*, José Aguirre, MD^*, Jianhua Feng, MD, PhD^*, Min Zhu, PhD^*, Marc Suter, MD^*, Donat R. Spahn, MD^*, Luc Härter, PhD, and Michael Zaugg, MD^*

From the *Institute of Anesthesiology; and Department of Trauma Surgery, University Hospital Zurich, Switzerland.

Address correspondence to Michael Zaugg, MD, Institute of Anesthesiology, E-HOF, University Hospital Zurich and, Zurich Center for Integrative Human Physiology ZIHP, University of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland. Address e-mail to michael.zaugg{at}usz.ch.

BACKGROUND: Late preconditioning by volatile anesthetics evolves in response to transcriptional changes. We hypothesized that sevoflurane inhalation would modify the transcriptome in human blood and modulate the expression of adhesion molecules in white blood cells consistent with the occurrence of a late preconditioning phase.

METHODS: Five healthy male subjects inhaled sevoflurane at an end-tidal concentration of 0.5%–1.0% for 60 min. Venous blood samples were collected at baseline, after 15 and 60 min of inhalation, and 6, 24, 48, and 72 h thereafter and immediately processed for flow cytometry and mRNA extraction and hybridization to Affymetrix U133 Plus 2.0 microarrays. Data were analyzed using Significance Analysis of Microarray and Gene Set Enrichment Analysis and confirmed by real-time reverse transcription polymerase chain reaction. L-selectin (CD62L) and ß₂-integrin (CD11b) expression was determined on granulocytes and monocytes using flow cytometry.

RESULTS: Sevoflurane inhalation rapidly and markedly altered gene expression in white blood cells. Key transcripts potentially involved in late preconditioning or organ protection including paraoxonase, 12-lipoxygenase, heat shock protein 40, chemokine ligand 5, and phosphodiesterase 5A were regulated in response to sevoflurane. Sevoflurane further decreased transcripts involved in peroxisome proliferator-activated receptor coactivator-1 (PGC-1) signaling and fatty acid oxidation. Reduced L-selectin (CD62L) expression on granulocytes accompanied with increased resistance to inflammatory activation was present at 24 to 48 h after sevoflurane exposure.

CONCLUSIONS: Sevoflurane at subanesthetic concentrations modifies blood transcriptome and decreases the expression of the proinflammatory L-selectin (CD62L), consistent with a "second window of protection" in humans.

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