Abstract

Age/gender may likely influence the course of septic complications after trauma. We aimed to characterize the influence of age/gender on the response of circulating cytokines, cells and organ function in post-traumatic sepsis. We additionally tested whether post-traumatic responses alone can accurately predict outcomes in subsequent post-traumatic sepsis. A mouse 2-hit model of trauma/hemorrhage (TH, 1st hit) and cecal ligation and puncture (CLP, 2nd hit) was employed. 3, 15 and 20 month (m) old female (♀) and male (♂) CD-1 mice underwent sublethal TH followed by CLP 2 days later. Blood was sampled daily until day 6 post-TH and survival was followed for 16 days. To compare general response patterns among groups, we calculated two scores: the inflammatory response (including KC, MIP-1α, TNFα, MCP-1, IFNγ, IL-1β,-5,-6,-10) and the organ dysfunction score (Urea, ALT, AST and LDH). Moreover, mice were retrospectively divided into survivors (SUR) and dying (DIE) based on post-CLP outcome. In general, females survived better than males and their survival did not correspond to any specific estrus cycle phase. Pre-CLP phase: the post-TH inflammatory score was weakest in 3 m♂ but there were no changes among remaining groups (similar lack of differences in the organ dysfunction score). TH induced a 40% increase of IFNγ, MIP-1α and IL-5 in 15 m♂ SUR (vs. DIE) but predictive accuracy for post-CLP outcomes was moderate. Post-CLP phase: while stable in males, inflammatory response score in 15 m and 20 m females decreased with age at day 1 and 2 post-CLP. SUR vs. DIE differences in inflammatory and organ dysfunction score were evident but their magnitude was comparable across age/gender. Nearly identical activation of the humoral inflammatory and organ function compartments, both across groups and according to sepsis severity, suggests that they are not directly responsible for the age/gender-dependent disparity in TH-CLP survival in the studied young-to-mature population.

Highlights

  • Trauma is one of the leading causes of morbidity and mortality in the young and adult populations in the United States and Europe [1,2]

  • Age and gender did not modify the global inflammatory response induced by trauma/hemorrhage

  • As oscillation of circulating estrogen is tightly correlated to ovulation, we aimed to investigate whether the estrus cycle status was related to survival after TH-cecal ligation and puncture (CLP)

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Summary

Introduction

Trauma is one of the leading causes of morbidity and mortality in the young and adult populations in the United States and Europe [1,2]. While trauma induces the release of local and systemic mediators to initiate tissue repair and support hemostasis and wound healing, primary hemodynamic responses aim to compensate the blood loss by an increase of heart rate and vascular resistance to avoid a state of hypovolemic shock [3,4]. These mechanisms represent a major challenge to the patient’s immuno-inflammatory system and can potentially impair his/her immune functions predisposing such an individual towards secondary complications including sepsis. The correlation between injury severity and increased risk of developing sepsis remains strong [5], and the ICU admission rates and mortality (94% and 40%) are significantly higher in trauma patients who develop sepsis compared to their non-septic counterparts [5]

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