Tumor necrosis factor-alpha modulates the selective interference of hypnotics and sedatives to suppress N-formyl-methionyl-leucyl-phenylalanine-induced oxidative burst formation in neutrophils.
OBJECTIVE
To clarify whether tumor necrosis factor (TNF)-alpha modulates the inhibitory effect of clinically applied hypnotics and sedatives on neutrophil function.


METHODS
Prospective, randomized, controlled, dose response, in vitro study.


METHODS
A university research laboratory.


METHODS
Neutrophils from healthy human volunteers.


RESULTS
Neutrophils were primed by incubation with TNF-alpha (25 ng/mL) for 15 mins. Subsequently, TNF-alpha-primed neutrophils were incubated with two concentrations of commercially available drug preparations and drug-free solutions, respectively. The following commercially available preparations of hypnotics and sedatives as well as their corresponding drug-free solutions were tested: methohexital, thiopental, midazolam, diazepam, etomidate, and propofol. The production of oxygen radicals was initiated by adding N-formyl-methionyl-leucyl-phenylalanine (FMLP) 10(-7) mol/L and detected by luminol-enhanced chemiluminescence measurements for 15 mins. Within the range of therapeutic plasma concentrations, only thiopental, diazepam, and propofol suppressed chemiluminescence of unprimed neutrophils. Additionally, propofol alone suppressed TNF-alpha-primed neutrophils. Hypnotics and sedatives were unable to suppress oxygen radical production of TNF-alpha-primed neutrophils below the level of their control activity, measured in FMLP-induced unprimed neutrophils in the absence of the respective drug or drug-free solution. However, the effect of etomidate could not be evaluated secondarily to effects mediated by its drug-free solution. In a cell-free chemiluminescence system, thiopental and propofol demonstrated scavenging of oxygen free radicals.


CONCLUSIONS
Priming with TNF-alpha counteracts the inhibitory effect by certain drugs for oxygen radical formation by FMLP-stimulated neutrophils. Thus, TNF-alpha plus FMLP mediate additive effects in stimulating oxygen radical formation in neutrophils. The following drugs dose-dependently interfere with these activating pathways: thiopental, diazepam, and propofol. Additionally, thiopental and propofol have efficient oxygen-scavenging properties and may attenuate radical-mediated tissue destruction in hyperinflammatory syndromes.
Weiss
M
M
Department of Anesthesiology, Heinrich-Heine-Universität, Düsseldorf, Germany.
Buhl
R
R
Medve
M
M
Schneider
E M
EM
D016166:Free Radical Scavengers; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D006993:Hypnotics and Sedatives / Q000378:metabolism* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology*; D016897:Respiratory Burst / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016166:Free Radical Scavengers; D005609:Free Radicals; D006993:Hypnotics and Sedatives; D014409:Tumor Necrosis Factor-alpha; D009240:N-Formylmethionine Leucyl-Phenylalanine