Sex Differences in the Oxidative Stress and Inflammation Response During and After Simulated Hemorrhage in Humans

Abstract

IntroductionHemorrhage (i.e., massive blood loss) induces an oxidative stress and inflammatory response that can persist even following hemostasis and resuscitation. These responses can result in tissue and organ damage if therapeutic inventions are delayed. Pre‐menopausal females exhibit a survival advantage following hemorrhage compared to males of a similar age. The role of oxidative stress and inflammation on increased survival from blood loss in young females is under investigation. Examining the potential mechanisms underpinning this survival advantage following hemorrhage may facilitate the development of sex‐specific therapies. In our laboratory, we utilize lower body negative pressure (LBNP) to simulate blood loss in conscious human subjects. In this study, we hypothesized that young males would elicit a greater oxidative stress and inflammatory response compared to young females, both during and after a simulated hemorrhage via LBNP.MethodsYoung, healthy human subjects (10F; 10M) participated in a stepwise‐LBNP protocol to presyncope. Stroke volume was estimated via finger photoplethysmography as a marker of central hypovolemia (indexed to body surface area). Venous blood samples were collected at baseline, at the onset of presyncope, and 60‐min into recovery (i.e., following “resuscitation”). The oxidative stress response was assessed via measurement of circulating F2‐Isoprostanes (F2‐IsoP) using gas chromatography‐negative ion chemical ionization‐mass spectrometry. The inflammatory response was assessed via measurement of circulating interleukin (IL)‐6 and IL‐10 using a MSD® Multiplex assay. Unpaired t‐tests were used to compare LBNP tolerance and stroke volume responses between male and female subjects. Two factor (time and sex) linear mixed model analyses with repeated measures were performed for all other comparisons, followed by Holm‐corrected post‐hoc tests. All data are represented as mean ± SE.ResultsLBNP tolerance time was similar between male and female subjects (Males, 1592 ± 124 s vs. Females, 1437 ± 113 s; P=0.37), and stroke volume index decreased by a similar magnitude at presyncope (Males, −50.2 ± 6.3% vs. Females, −49.4 ± 3.2%; P = 0.87). There was no effect of time or sex on [F2‐IsoP] or on the %Δ [F2‐IsoP] during or after LBNP (P ≥ 0.12). However, male subjects exhibited a greater increase in both the %Δ [IL‐6] and %Δ [IL‐10] compared to female subjects at the 60‐min recovery time point (IL‐6: Males, 101.4 ± 138.9% vs. Females, 12.3 ± 34.0%; P = 0.06. IL‐10: Males, 71.1 ± 133.3% vs. Females, −2.2 ± 11.8%; P = 0.06).ConclusionThese data suggest that there may be a sex difference in the inflammatory response to blood loss and subsequent fluid resuscitation. Future clinical studies should continue to explore sex differences in inflammatory responses to actual blood loss, and tailor therapeutic interventions accordingly.Support or Funding InformationWilliam and Ella Owens Medical Research Foundation