Insight into the beneficial immunomodulatory mechanism of the sevoflurane metabolite hexafluoro-2-propanol in a rat model of endotoxaemia
M. Urner
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
M. Urner and M. Schläpfer contributed equally to this work as first authors.
Search for more papers by this authorM. Schläpfer
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
M. Urner and M. Schläpfer contributed equally to this work as first authors.
Search for more papers by this authorI. K. Herrmann
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland
Search for more papers by this authorM. Hasler
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland
Search for more papers by this authorR. R. Schimmer
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
Search for more papers by this authorC. Booy
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
Search for more papers by this authorB. Roth Z'graggen
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
Functional Genomics Center Zurich, University of Zurich, Zurich, Switzerland
Search for more papers by this authorH. Rehrauer
Functional Genomics Center Zurich, University of Zurich, Zurich, Switzerland
Search for more papers by this authorF. Aigner
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
Search for more papers by this authorR. D. Minshall
Department of Anesthesiology, University of Illinois Chicago, Chicago, IL, USA
Search for more papers by this authorW. J. Stark
Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, Zurich, Switzerland
W. J. Stark and B. Beck-Schimmer contributed equally to this work as senior authors.
Search for more papers by this authorCorresponding Author
B. Beck-Schimmer
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
W. J. Stark and B. Beck-Schimmer contributed equally to this work as senior authors.
Correspondence: B. Beck-Schimmer, University Hospital Zurich, Institute of Anesthesiology, Rämistrasse 100, CH-8091 Zurich, Switzerland. E-mail: [email protected]Search for more papers by this authorM. Urner
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
M. Urner and M. Schläpfer contributed equally to this work as first authors.
Search for more papers by this authorM. Schläpfer
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
M. Urner and M. Schläpfer contributed equally to this work as first authors.
Search for more papers by this authorI. K. Herrmann
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland
Search for more papers by this authorM. Hasler
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland
Search for more papers by this authorR. R. Schimmer
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
Search for more papers by this authorC. Booy
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
Search for more papers by this authorB. Roth Z'graggen
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
Functional Genomics Center Zurich, University of Zurich, Zurich, Switzerland
Search for more papers by this authorH. Rehrauer
Functional Genomics Center Zurich, University of Zurich, Zurich, Switzerland
Search for more papers by this authorF. Aigner
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
Search for more papers by this authorR. D. Minshall
Department of Anesthesiology, University of Illinois Chicago, Chicago, IL, USA
Search for more papers by this authorW. J. Stark
Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, Zurich, Switzerland
W. J. Stark and B. Beck-Schimmer contributed equally to this work as senior authors.
Search for more papers by this authorCorresponding Author
B. Beck-Schimmer
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
W. J. Stark and B. Beck-Schimmer contributed equally to this work as senior authors.
Correspondence: B. Beck-Schimmer, University Hospital Zurich, Institute of Anesthesiology, Rämistrasse 100, CH-8091 Zurich, Switzerland. E-mail: [email protected]Search for more papers by this authorSummary
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.
Supporting Information
Additional Supporting information may be found in the online version of this article at the publisher's web-site:
| Filename | Description |
|---|---|
| cei12648-sup-0001-suppinfo01.doc962 KB |
Fig. S1. GeneGo metacore pathway analysis. Table S1. Linear regressions on plasma inflammatory mediators and haemodynamics Table S2. Linear regressions on inflammatory mediator, organ damage marker as well as organ function of the kidney Table S3. Linear regressions on inflammatory mediator and organ damage marker of the liver Table S4. Linear regressions on inflammatory mediator, organ damage marker as well as organ function of the lung Table S5. Linear regressions on inflammatory mediator and organ damage marker of the spleen Table S6. Linear regressions on acid/base status and plasma electrolytes Table S7. Linear regression on inflammatory response in human microvascular endothelial cells (HMVEC) after stimulation with tumour necrosis factor-α (TNF-α) Table S8. Linear regression on inflammatory response in human microvascular endothelial cells (HMVEC) after stimulation with phorbol 12-myristate 13-acetate (PMA) |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1 Lagu T, Rothberg MB, Shieh MS, Pekow PS, Steingrub JS, Lindenauer PK. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med 2012; 40: 754–61.
- 2 Gaieski DF, Mikkelsen ME, Band RA et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010; 38: 1045–53.
- 3 Dellinger RP, Levy MM, Rhodes A et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41: 580–637.
- 4 Landoni G, Fochi O, Tritapepe L et al. Cardiac protection by volatile anesthetics. A review. Minerva Anestesiol 2009; 75: 269–73.
- 5 Beck-Schimmer B, Breitenstein S, Urech S et al. A randomized controlled trial on pharmacological preconditioning in liver surgery using a volatile anesthetic. Ann Surg 2008; 248: 909–18.
- 6 Ferrero ME, Marni A, Gaja G, Salari PC, Tiengo M. Conditioning of immune response by anesthetics. Ann NY Acad Sci 1992; 650: 331–6.
- 7 Kharasch ED, Coopersmith CM. Sleeping to survive? The impact of volatile anesthetics on mortality in sepsis. Anesthesiology 2013; 119: 755–6.
- 8 De Conno E, Steurer MP, Wittlinger M et al. Anesthetic-induced improvement of the inflammatory response to one-lung ventilation. Anesthesiology 2009; 110: 1316–26.
- 9 Julier K, da Silva R, Garcia C et al. Preconditioning by sevoflurane decreases biochemical markers for myocardial and renal dysfunction in coronary artery bypass graft surgery: a double-blinded, placebo-controlled, multicenter study. Anesthesiology 2003; 98: 1315–27.
- 10 Herrmann IK, Castellon M, Schwartz DE et al. Volatile anesthetics improve survival after cecal ligation and puncture. Anesthesiology 2013; 119: 901–6.
- 11 Lee HT, Emala CW, Joo JD, Kim M. Isoflurane improves survival and protects against renal and hepatic injury in murine septic peritonitis. Shock 2007; 27: 373–9.
- 12 Lucchinetti E, Schaub MC, Zaugg M. Emulsified intravenous versus evaporated inhaled isoflurane for heart protection: old wine in a new bottle or true innovation? Anesth Analg 2008; 106: 1346–9.
- 13 Urner M, Limbach LK, Herrmann IK et al. Fluorinated groups mediate the immunomodulatory effects of volatile anesthetics in acute cell injury. Am J Respir Cell Mol Biol 2011; 45: 617–24.
- 14 Herrmann IK, Castellon M, Schwartz DE et al. Intravenous application of a primary sevoflurane metabolite improves outcome in murine septic peritonitis: first results. PLOS ONE 2013; 8: e72057.
- 15 Doi K, Leelahavanichkul A, Yuen PS, Star RA. Animal models of sepsis and sepsis-induced kidney injury. J Clin Invest 2009; 119: 2868–78.
- 16 Beutler B. Tlr4: central component of the sole mammalian LPS sensor. Curr Opin Immunol 2000; 12: 20–6.
- 17 Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila toll protein signals activation of adaptive immunity. Nature 1997; 388: 394–7.
- 18 Voigtsberger S, Lachmann RA, Leutert AC et al. Sevoflurane ameliorates gas exchange and attenuates lung damage in experimental lipopolysaccharide-induced lung injury. Anesthesiology 2009; 111: 1238–48.
- 19 Urner M, Limbach LK, Herrmann IK et al. Fluorinated groups mediate the immunomodulatory effects of volatile anesthetics in acute cell injury. Am J Respir Cell Mol Biol 2011; 45: 617–24.
- 20 Kharasch ED, Karol MD, Lanni C, Sawchuk R. Clinical sevoflurane metabolism and disposition. I. Sevoflurane and metabolite pharmacokinetics. Anesthesiology 1995; 82: 1369–78.
- 21 Bozza FA, Salluh JI, Japiassu AM et al. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care 2007; 11: R49.
- 22 Damas P, Ledoux D, Nys M et al. Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 1992; 215: 356–62.
- 23 Vermont CL, Hazelzet JA, de Kleijn ED, van den Dobbelsteen GP, de Groot R. CC and CXC chemokine levels in children with meningococcal sepsis accurately predict mortality and disease severity. Crit Care 2006; 10: R33.
- 24 Hewett JA, Schultze AE, VanCise S, Roth RA. Neutrophil depletion protects against liver injury from bacterial endotoxin. Lab Invest 1992; 66: 347–61.
- 25 Guidet B, Aegerter P, Gauzit R Meshaka P, Dreyfuss D, CUB-Réa Study Group. Incidence and impact of organ dysfunctions associated with sepsis. Chest 2005; 127: 942–51.
- 26 Dear JW, Yasuda H, Hu X et al. Sepsis-induced organ failure is mediated by different pathways in the kidney and liver: acute renal failure is dependent on MyD88 but not renal cell apoptosis. Kidney Int 2006; 69: 832–6.
- 27 Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008; 8: 776–87.
- 28 O'Seaghdha CM, Hwang SJ, Larson MG, Meigs JB, Vasan RS, Fox CS. Analysis of a urinary biomarker panel for incident kidney disease and clinical outcomes. J Am Soc Nephrol 2013; 24: 1880–8.
- 29 Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem 1982; 257: 7847–51.
- 30 Blumberg PM. Protein kinase C as the receptor for the phorbol ester tumor promoters: sixth Rhoads memorial award lecture. Cancer Res 1988; 48: 1–8.
- 31 Voigtsberger S, Lachmann RA, Leutert AC et al. Sevoflurane ameliorates gas exchange and attenuates lung damage in experimental lipopolysaccharide-induced lung injury. Anesthesiology 2009; 111: 1238–48.
- 32 Hotchkiss RS, Tinsley KW, Swanson PE et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol 2001; 166: 6952–63.
- 33 Hotchkiss RS, Nicholson DW. Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol 2006; 6: 813–22.
- 34 Braun JS, Novak R, Herzog KH, Bodner SM, Cleveland JL, Tuomanen EI. Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nat Med 1999; 5: 298–302.
- 35 Hotchkiss RS, Chang KC, Swanson PE et al. Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat Immunol 2000; 1: 496–501.
- 36 Zhong C, Zhou Y, Liu H. Nuclear factor kappaB and anesthetic preconditioning during myocardial ischemia–reperfusion. Anesthesiology 2004; 100: 540–6.
- 37 Loop T, Scheiermann P, Doviakue D et al. Sevoflurane inhibits phorbol-myristate-acetate-induced activator protein-1 activation in human T lymphocytes in vitro: potential role of the p38-stress kinase pathway. Anesthesiology 2004; 101: 710–21.
- 38 Buras JA, Holzmann B, Sitkovsky M. Animal models of sepsis: setting the stage. Nat Rev Drug Discov 2005; 4: 854–65.
- 39 Zeni F, Freeman B, Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med 1997; 25: 1095–100.
- 40 Laterre PF, Levy H, Clermont G et al. Hospital mortality and resource use in subgroups of the recombinant human activated protein C worldwide evaluation in severe sepsis (PROWESS) trial. Crit Care Med 2004; 32: 2207–18.
- 41 Kharasch ED, Coopersmith CM. Sleeping to survive?: The impact of volatile anesthetics on mortality in sepsis. Anesthesiology 2013; 119: 755–6.
