Sevoflurane Promotes Bactericidal Properties of Macrophages through Enhanced Inducible Nitric Oxide Synthase Expression in Male Mice
Thomas J. Gerber, M.D.; Valérie C. O. Fehr, M.Med.; Suellen D. S. Oliveira, Ph.D.; Guochang Hu, M.D., Ph.D.; Randal Dull, M.D., Ph.D.; et alMarcelo G. Bonini, Ph.D.; Beatrice Beck-Schimmer, M.D.; Richard D. Minshall, Ph.D.
 Author Notes
From the Departments Anesthesiology (T.J.G., V.C.O.F., S.D.S.O., G.H., R.D., B.B.-S., R.D.M.), Medicine (M.G.B.), and Pharmacology (R.D.M.), University of Illinois at Chicago, Chicago, Illinois; and Institute of Anesthesiology (V.C.O.F., B.B.-S.) and the Institute of Physiology and Zurich Center for Integrative Human Physiology (T.J.G., V.C.O.F., B.B.-S.), University of Zurich, Zurich, Switzerland.
Part of the work presented in this article has been presented at the Swiss Society of Anesthesiology and Resuscitation Annual Conference in Basel, Switzerland, November 4, 2016; the College of Medicine Research Forum, University of Illinois at Chicago, Chicago, Illinois, November 18, 2016; and the International Anesthesia Research Society Annual Conference in Montreal, Quebec, Canada, May 21, 2019.
T.J.G. and V.C.O.F. as first authors as well as B.B.S. and R.D.M. as last authors contributed equally to this article.
Submitted for publication December 6, 2018. Accepted for publication August 19, 2019.
Correspondence: Address correspondence to Dr. Beck-Schimmer: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Institute of Anesthesiology, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland. beatrice.beckschimmer@uzh.ch. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Anesthesiology Newly Published on October 24, 2019. doi:10.1097/ALN.0000000000002992

Abstract
Editor’s Perspective:

What We Already Know about This Topic:

Sevoflurane has antiinflammatory properties, but less is known about effects on infectious inflammation

Sevoflurane effects on macrophage function in inflammation are not well understood

What This Article Tells Us That Is New:

In a lipopolysaccharide model of inflammation, sevoflurane increased mouse macrophage nitric oxide synthase activity and bacteria phagocytosis in vitro and in vivo

These effects were abolished by pharmacologically inhibiting nitric oxide synthase expression

In endotoxemia in mice, sevoflurane had bactericidal effects

Background: Sevoflurane with its antiinflammatory properties has shown to decrease mortality in animal models of sepsis. However, the underlying mechanism of its beneficial effect in this inflammatory scenario remains poorly understood. Macrophages play an important role in the early stage of sepsis as they are tasked with eliminating invading microbes and also attracting other immune cells by the release of proinflammatory cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-α. Thus, the authors hypothesized that sevoflurane mitigates the proinflammatory response of macrophages, while maintaining their bactericidal properties.

Methods: Murine bone marrow–derived macrophages were stimulated in vitro with lipopolysaccharide in the presence and absence of 2% sevoflurane. Expression of cytokines and inducible NO synthase as well as uptake of fluorescently labeled Escherichia coli (E. coli) were measured. The in vivo endotoxemia model consisted of an intraperitoneal lipopolysaccharide injection after anesthesia with either ketamine and xylazine or 4% sevoflurane. Male mice (n = 6 per group) were observed for a total of 20 h. During the last 30 min fluorescently labeled E. coli were intraperitoneally injected. Peritoneal cells were extracted by peritoneal lavage and inducible NO synthase expression as well as E. coli uptake by peritoneal macrophages was determined using flow cytometry.

Results: In vitro, sevoflurane enhanced lipopolysaccharide-induced inducible NO synthase expression after 8 h by 466% and increased macrophage uptake of fluorescently labeled E. coli by 70% compared with vehicle-treated controls. Inhibiting inducible NO synthase expression pharmacologically abolished this increase in bacteria uptake. In vivo, inducible NO synthase expression was increased by 669% and phagocytosis of E. coli by 49% compared with the control group.

Conclusions: Sevoflurane enhances phagocytosis of bacteria by lipopolysaccharide-challenged macrophages in vitro and in vivo via an inducible NO synthase–dependent mechanism. Thus, sevoflurane potentiates bactericidal and antiinflammatory host-defense mechanisms in endotoxemia.