Gender differences in the innate immune response and vascular reactivity following the administration of endotoxin to human volunteers.
OBJECTIVE
To determine gender differences in the innate immune response and vascular reactivity during human endotoxemia.


METHODS
Clinical experimental study.


METHODS
University medical center intensive care research unit.


METHODS
Fifteen female and 15 male volunteers.


METHODS
Intravenous injection of 2 ng/kg Escherichia coli lipopolysaccharide.


RESULTS
C-reactive protein, leukocytes, and cytokines were measured at regular time intervals as indicators of inflammation. Heart rate and blood pressure were continuously monitored. Forearm blood flow and the responsiveness of forearm vessels to the intrabrachial infusion of norepinephrine (1-3-10-30 ng/min/dL) were measured before and 4 hrs after the administration of endotoxin using venous occlusion plethysmography. Differences were tested with repeated-measures analysis of variance. Females showed a more proinflammatory response to lipopolysaccharide than males, illustrated by a higher rise in C-reactive protein (42 +/- 3 vs. 29 +/- 3 mg/L, p = .002) and more leukocyte sequestration (leukopenia 1.8 +/- 0.1 x 10 vs. 2.4 +/- 0.1 x 10, p = .003). The increase in cytokine levels showed a more proinflammatory pattern in females as reflected by a higher increase in tumor necrosis factor-alpha (965 +/- 193 vs. 411 +/- 35 pg/mL, p < .0001), whereas the increase of the anti-inflammatory interleukin-10 was not significantly different (95 +/- 15 pg/mL in females vs. 129 +/- 15 pg/mL in males, p = .288). Females exhibited higher baseline levels (9.9 +/- 1.1 vs. 7.0 +/- 0.8 pg/mL in males, p = .042) and an augmented increase in lipopolysaccharide-binding protein, which may explain the more pronounced inflammatory response in females. The lipopolysaccharide-induced change in heart rate was not significantly different between the genders, whereas blood pressure decreased more in females (p < .0001). Lipopolysaccharide administration significantly attenuated the norepinephrine sensitivity in males (p = .002), whereas no lipopolysaccharide-induced effect was observed in females (p = .552; difference between groups, p = .045).


CONCLUSIONS
During experimental human endotoxemia, females showed a more pronounced proinflammatory innate immune response associated with less attenuation of norepinephrine sensitivity. These findings may be relevant in view of the profound and incompletely explained differences in incidence and outcome of sepsis among male and female patients.
van Eijk
Lucas T
LT
Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Dorresteijn
Mirrin J
MJ
Smits
Paul
P
van der Hoeven
Johannes G
JG
Netea
Mihai G
MG
Pickkers
Peter
P
D000328:Adult; D001775:Blood Circulation; D001794:Blood Pressure; D002097:C-Reactive Protein / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000276:immunology* / Q000503:physiopathology; D004926:Escherichia coli; D005260:Female; D005334:Fever / Q000276:immunology; D005542:Forearm / Q000098:blood supply; D006339:Heart Rate; D006801:Humans; D007113:Immunity, Innate; D007362:Intensive Care Units; D007962:Leukocytes / Q000276:immunology; D008070:Lipopolysaccharides / Q000097:blood / Q000276:immunology*; D008297:Male; D012039:Regional Blood Flow; D012737:Sex Factors
D016207:Cytokines; D008070:Lipopolysaccharides; D002097:C-Reactive Protein