Fluorinated Groups Mediate the Immunomodulatory Effects of Volatile Anesthetics in Acute Cell Injury

Abstract

Volatile anesthetics are known to attenuate inflammatory response and tissue damage markers in acute organ injury. It is unclear whether these beneficial effects of volatile anesthetics are mediated by the ether basic structure or by characteristics of their halogenations. We describe in an in vitro model of acute inflammation in pulmonary cells that halogenation (fluorinated carbon groups) is responsible for the immunomodulatory effects. The inflammatory response after coexposure to endotoxin and sevoflurane, diethyl-ether, or various water-soluble molecules carrying trifluorinated carbon (CF(3)) groups was evaluated in pulmonary epithelial and endothelial cells and in neutrophils. In epithelial and endothelial cells, expression of inflammatory mediators to LPS stimulation was dose-dependently decreased upon exposure to sevoflurane and other molecules with CF(3) groups. This was not observed for diethyl-ether or structure-similar nonfluorinated molecules. In neutrophils, chemotactic activity, as well as expression of surface CD11b and CD62L, was positively modified by molecules carrying CF(3) groups. Cytotoxicity could be excluded. These findings for the first time reveal in an in vitro model of acute inflammation that the immunomodulatory effects are not limited to volatile anesthetics but are associated with a much broader class of CF(3) group-containing molecules. The immunomodulatory effects could now be provided in a hydrophilic, injectable formulation for the treatment of patients suffering from acute organ injury, such as acute lung injury, in environments not suitable for volatile anesthetics.

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

“…The blocks were again randomized into the following groups: (1) LPS group (n = 10), which received intravenous 1 mg/kg Escherichia coli endotoxin [LPS, E. coli endotoxin serotype 055:B5; Sigma-Aldrich, Buchs, Switzerland; dissolved at a concentration of 1 mg/ml in phosphate-buffered saline (PBS) Kantonsapotheke Zurich, Zurich, Switzerland]; (2) LPS1HFIP group (n = 7), which was treated identically to the LPS group with the additional administration of 67 mg/kg HFIP (SigmaAldrich) in Ringer's lactate for 30 min after LPS injection; (3) LPS1sevoflurane group (n = 8), which was treated identically to the LPS group but with the additional administration of sevoflurane (Sevorane; Abott, Baar, Switzerland) using the Anaesthetic Conserving Device (AnaConDa; Sedana Medical, Uppsala, Sweden) for 30 min after LPS injection [18] while propofol infusion was stopped and reinitiated after the 30-min sevoflurane application; (4) control group with PBS instead of LPS (n = 5); (5) HFIP group in which animals received PBS and 67 mg/kg HFIP (n = 5). Based on results from in-vitro studies [19], we decided empirically to administer a dose of 67 mg/kg HFIP to rats, which corresponds to 0Á39 mmol/kg total body weight (BW) or 4 mmol/l blood volume. This dose is comparable to previous experiments [14,19] and significantly lower than the median lethal dose (LD 50 ) (approximately 180 mg/kg in mice when administered intravenously) [14].…”

“…For gene expression analysis, cells were exposed for 6 h to 20 mg/ml LPS (dissolved in PBS) from E. coli serotype 055:B5 (Sigma-Aldrich) to induce an inflammatory response (control cells were incubated with PBS) and co-exposed to 8 mmol/l HFIP (Sigma-Aldrich), as in our previous study [13] (Fig. 1b).…”

“…Luciferase assay of activator protein-1 (AP-1) and NF-jB activity Endothelial cells were grown in a 96-well plate to 70% confluence and starved overnight as described [19]. Diluted Plus Reagent (1 : 40 in Optimem, both from Invitrogen) was mixed with 100 ng DNA per well (Cignal Reporter Assay; Quiagen, Venlo, the Netherlands) and added to the same volume of diluted lipofectamine LTX (1 : 12Á5 in Optimem, both from Invitrogen).…”

Volatile Anesthetics and AKI

“…45 In vitro studies in epithelial and endothelial cells suggest that halogenation (fluorinated carbon groups) is responsible for the immunomodulatory effects of volatile anesthetics. 46 The trifluorocarbon (CF 3 ) molecule, which is shared in all newer volatile anesthetics, has been suggested as the specific molecular group of a volatile anesthetic that exerts immunomodulatory effects (Figure 2). In pulmonary epithelial and endothelial cells, modulation of chemical structures of volatile anesthetics showed that the CF 3 molecular group is required for decreasing multiple proinflammatory chemokine and cytokine markers after LPS treatment.…”

The Utility of a Nonhuman Primate Model for Assessing Anesthetic-Induced Developmental Neurotoxicity

“…It is possible that they might come from inflamed cells in the CNS via leakage through a compromised blood-brain barrier (BBB) or directly from peripheral immune cells sensitive to sevoflurane. It has been postulated that the immunomodulatory effects of volatile anesthetics on peripheral immune cells can be mediated by trifluorocarbon (CF 3 ) groups found on halogenated molecules [40].…”