Insight into the beneficial immunomodulatory mechanism of the sevoflurane metabolite hexafluoro-2-propanol in a rat model of endotoxaemia

Abstract

SummaryVolatile 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 endpoints. 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-jB) 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.

Hexafluoroisopropanol as a highly versatile solvent

“…This is thought to be due to an altered immune response which reduces the damaging inflammatory response in such situations. 81 Early work by Urner showed that the immunomodulatory effects of volatile anaesthetics are due to the presence of fluorinated carbon groups 82 and subsequently, Herrmann and coworkers postulated that HFIP could elicit a similar immunomodulatory response. Intraveneous administration of HFIP was shown to significantly improve survival rate in murine models of cecal ligation and puncture.…”

“…Intraveneous administration of HFIP was shown to significantly improve survival rate in murine models of cecal ligation and puncture. 81 The most recent work demonstrates the effect of intraveneous HFIP administration in attenuating inflammation in rats, and found it to be equal, and in some measures superior, to inhaled sevoflurane. 82 This effect was attributed to reduced levels of proinflammatory mediators in plasma and tissue which leads to decreased white blood cell (neutrophil) invasion at the site of injury, hence attenuating apoptosis in internal organs.…”

Sevoflurane attenuates systemic inflammation compared with propofol, but does not modulate neuro-inflammation

“…Reverse transcription and real-time quantitative PCR for CINC-1, MCP-1, IL-6, intercellular adhesion molecule-1 (ICAM-1) and TGFb1 were performed as previously described. 28 Details of forward and reverse primers as well as the probes used can be found in Table 1.…”

Volatile Anesthetic Sevoflurane Precursor 1,1,1,3,3,3-Hexafluoro-2-Propanol (HFIP) Exerts an Anti-Prion Activity in Prion-Infected Culture Cells

“…No toxicity for HFIP at clinically derived concentrations has been reported to date. Besides, HFIP suppresses endotoxin-stimulated inflammatory mediator secretion and improves the survival rate of septic peritonitis mice models [ 20 ]. Fluorinated alcohols, such as HFIP, have a particularly strong protein-denaturing activity and break the β-sheet structure leading to α-helix.…”