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Gender differences in the innate immune response and vascular reactivity following the administration of endotoxin to human volunteers*

van Eijk, Lucas T. MD; Dorresteijn, Mirrin J. MD; Smits, Paul MD, PhD; van der Hoeven, Johannes G. MD, PhD; Netea, Mihai G. MD, PhD; Pickkers, Peter MD, PhD

doi: 10.1097/01.CCM.0000266534.14262.E8
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Objective: To determine gender differences in the innate immune response and vascular reactivity during human endotoxemia.

Design: Clinical experimental study.

Setting: University medical center intensive care research unit.

Subjects: Fifteen female and 15 male volunteers.

Interventions: Intravenous injection of 2 ng/kg Escherichia coli lipopolysaccharide.

Measurements and Main 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 × 109 vs. 2.4 ± 0.1 × 109, p = .003). The increase in cytokine levels showed a more proinflammatory pattern in females as reflected by a higher increase in tumor necrosis factor-α (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.

From the Departments of Intensive Care Medicine (LvE, MD, JvdH, PP), Pharmacology-Toxicology (LvE, PS, PP), and Internal Medicine (MN), and the Nijmegen University Center for Infectious Diseases (JvdH, MN), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Supported, in part, by clinical fellowship grant 907-00-056 (PP), Netherlands Organization for Scientific Research, The Hague, The Netherlands.

The authors have not disclosed any potential conflicts of interest.

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© 2007 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins