Sevoflurane Promotes Bactericidal Properties of Macrophages through Enhanced Inducible Nitric Oxide Synthase Expression in Male Mice
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Thomas J Gerber1, Valérie C O Fehr, Suellen D S Oliveira
1From 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.) Pharmacology (R.D.M.), University of Illinois at Chicago, Chicago, Illinois Institute of Anesthesiology (V.C.O.F., B.B.-S.) 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.
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.
Insights
Sevoflurane boosts macrophage ability to engulf bacteria, a key defense against sepsis. This effect is dependent on inducible nitric oxide synthase, enhancing both bacterial clearance and anti-inflammatory responses.
Area of Science:
- Anesthesiology
- Immunology
- Microbiology
Background:
- Sepsis is a life-threatening condition where understanding host-defense mechanisms is crucial.
- Macrophages are key immune cells in early sepsis, responsible for pathogen elimination and immune cell recruitment.
- Sevoflurane's anti-inflammatory properties may reduce sepsis mortality, but its precise mechanism is unclear.
Purpose of the Study:
- To investigate if sevoflurane enhances macrophage bactericidal properties while mitigating pro-inflammatory responses.
- To elucidate the role of inducible nitric oxide synthase (iNOS) in sevoflurane's effects on macrophages during endotoxemia.
Main Methods:
- Murine bone marrow-derived macrophages were stimulated with lipopolysaccharide (LPS) and sevoflurane in vitro.
- In vivo endotoxemia model in mice using LPS, with anesthesia via ketamine/xylazine or sevoflurane.
- Quantification of cytokine expression, iNOS, and bacterial uptake (Escherichia coli) using flow cytometry.
Main Results:
- In vitro, sevoflurane significantly increased iNOS expression and bacterial uptake by macrophages.
- Pharmacological inhibition of iNOS abolished the enhanced bacterial uptake.
- In vivo, sevoflurane anesthesia increased iNOS expression and bacterial phagocytosis in mice.
Conclusions:
- Sevoflurane enhances bacterial phagocytosis by macrophages in an iNOS-dependent manner.
- Sevoflurane potentiates both bactericidal and anti-inflammatory host-defense mechanisms in endotoxemia.
- Findings suggest sevoflurane could be a therapeutic agent in managing sepsis.
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