Hemorrhagic Shock Induces a Rapid Transcriptomic Shift of the Immune Balance in Leukocytes after Experimental Multiple Injury.

Lisa Debler,Bettina Klohs,Karlheinz Holzmann,Tom Eirik Mollnes,Rebecca Halbgebauer,Annette Palmer,Markus Huber-Lang,Sonja Braumüller

doi:10.1155/2021/6654318

Abstract

The immune response following trauma represents a major driving force of organ dysfunction and poor outcome. Therefore, we investigated the influence of an additional hemorrhagic shock (HS) on the early posttraumatic immune dysbalance in the whole population of blood leukocytes. A well-established murine polytrauma (PT) model with or without an additional pressure-controlled HS (mean arterial pressure of 30 mmHg (±5 mmHg) for 60 mins, afterwards fluid resuscitation with balanced electrolyte solution four times the volume of blood drawn) was used. C57BL/6 mice were randomized into a control, PT, and PT + HS group with three animals in each group. Four hours after trauma, corresponding to three hours after induction of hemorrhage, RNA was isolated from all peripheral blood leukocytes, and a microarray analysis was performed. Enrichment analysis was conducted on selected genes strongly modulated by the HS. After additional HS in PT mice, the gene expression of pathways related to the innate immunity, such as IL-6 production, neutrophil chemotaxis, cell adhesion, and toll-like receptor signaling was upregulated, whereas pathways of the adaptive immune system, such as B- and T-cell activation as well as the MHC class II protein complex, were downregulated. These results demonstrate that an additional HS plays an important role in the immune dysregulation early after PT by shifting the balance to increased innate and reduced adaptive immune responses.

Highlights

Hemorrhagic shock (HS) is a form of hypovolemic shock caused by severe blood loss, resulting in oxygen demand surpassing oxygen supply at a cellular level
Concerning the posttraumatic immune response, Xiao et al showed that after critical injury, the expression of pathways involved in activation of pro- and anti-inflammatory innate immune reactions was strongly induced in peripheral blood leukocytes early after the insult, while pathways responsible for adaptive immunity were widely downregulated, in what was described as a “genomic storm.”
These new insights lead to a shift in paradigm from the understanding that trauma leads to a systemic inflammatory response syndrome (SIRS) temporally followed by a counteracting compensatory antiinflammatory response to a new hypothesis proposing rather a rapid induction of innate pro- and anti-inflammatory immune responses with a simultaneous impairment of adaptive responses after injury

Summary

Introduction

Hemorrhagic shock (HS) is a form of hypovolemic shock caused by severe blood loss, resulting in oxygen demand surpassing oxygen supply at a cellular level. Oxygen deprivation and a breakdown of blood-organ barriers lead to Mediators of Inflammation organ damage, and an additional release of the body’s own damage-associated molecular patterns (DAMPs) in response to tissue injury and hypoxia contributes to a systemic inflammatory response [6,7,8,9] These endogenous alarmins, which are released from the necrotic tissue as well as activated immune cells, further stimulate the cellular innate immunity via binding to surface pattern recognition receptors. Patients who suffered from complications showed a longer time until the genomic response returned to the baseline [12] These new insights lead to a shift in paradigm from the understanding that trauma leads to a systemic inflammatory response syndrome (SIRS) temporally followed by a counteracting compensatory antiinflammatory response to a new hypothesis proposing rather a rapid induction of innate pro- and anti-inflammatory immune responses with a simultaneous impairment of adaptive responses after injury. As a likely result of these alterations in the gene expression, different leukocyte subpopulations such as neutrophils, monocytes, and regulatory T-cells were described to be functionally impaired in the critically ill, resulting in an increased risk of secondary infection [16]

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Conclusion