Insight into the beneficial immunomodulatory mechanism of the sevoflurane metabolite hexafluoro-2-propanol in a rat model of endotoxaemia.
Volatile anaesthetics such as sevoflurane attenuate inflammatory processes, thereby impacting patient outcome significantly. Their inhalative administration is, however, strictly limited to controlled environments such as operating theatres, and thus an intravenously injectable immunomodulatory drug would offer distinct advantages. As protective effects of volatile anaesthetics have been associated with the presence of trifluorinated carbon groups in their basic structure, in this study we investigated the water-soluble sevoflurane metabolite hexafluoro-2-propanol (HFIP) as a potential immunomodulatory drug in a rat model of endotoxic shock. Male Wistar rats were subjected to intravenous lipopolysaccharide (LPS) and thereafter were treated with HFIP. Plasma and tissue inflammatory mediators, neutrophil invasion, tissue damage and haemodynamic stability were the dedicated end-points. In an endotoxin-induced endothelial cell injury model, underlying mechanisms were elucidated using gene expression and gene reporter analyses. HFIP reduced the systemic inflammatory response significantly and decreased endotoxin-induced tissue damage. Additionally, the LPS-provoked drop in blood pressure of animals was resolved by HFIP treatment. Pathway analysis revealed that the observed attenuation of the inflammatory process was associated with reduced nuclear factor kappa B (NF-κΒ) activation and suppression of its dependent transcripts. Taken together, intravenous administration of HFIP exerts promising immunomodulatory effects in endotoxaemic rats. The possibility of intravenous administration would overcome limitations of volatile anaesthetics, and thus HFIP might therefore represent an interesting future drug candidate for states of severe inflammation.
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.|Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
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M
Urner
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.|Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
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M
Schläpfer
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.
I K
IK
Herrmann
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.
M
M
Hasler
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
R R
RR
Schimmer
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.|Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
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C
Booy
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.|Functional Genomics Center Zurich, University of Zurich, Zurich, Switzerland.
B
B
Roth Z'graggen
Functional Genomics Center Zurich, University of Zurich, Zurich, Switzerland.
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H
Rehrauer
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
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F
Aigner
Department of Anesthesiology, University of Illinois Chicago, Chicago, IL, USA.
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RD
Minshall
Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, Zurich, Switzerland.
W J
WJ
Stark
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.|Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.|Department of Anesthesiology, University of Illinois Chicago, Chicago, IL, USA.
B
B
Beck-Schimmer
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D019446:Endotoxemia / Q000378:metabolism / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000378:metabolism / Q000517:prevention & control; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016014:Linear Models; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008738:Methyl Ethers / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D020005:Propanols / Q000378:metabolism / Q000494:pharmacology*; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077149:Sevoflurane; D012772:Shock, Septic / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D006845:Hydrocarbons, Fluorinated
D000276:Adjuvants, Immunologic; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008738:Methyl Ethers; D020005:Propanols; D000077149:Sevoflurane; C001337:hexafluoroisopropanol; D006845:Hydrocarbons, Fluorinated
anaesthesia; fluorinated carbon groups; inflammation; interleukin; sepsis