Hyperbaric Oxygen Reduces Production of Reactive Oxygen Species in Neutrophils from Polytraumatized Patients Yielding in the Inhibition of p38 MAP Kinase and Downstream Pathways.

Adnana Paunel-Görgülü,Deborah Grimberg-Peters,Martijn van Griensven,Joachim Windolf,Thorsten Wahlers,Carina Büren

doi:10.1371/journal.pone.0161343

Abstract

Trauma represents the leading cause of death among young people in western countries. Among the beneficial role of neutrophils in host defence, excessive priming and activation of neutrophils after major trauma lead to an overwhelming inflammatory response and secondary host tissue injury due to the release of toxic metabolites and enzymes. Hyperbaric oxygen (HBO) therapy has been proposed to possess antiinflammatory effects and might represent an appropriate therapeutic option to lower inflammation in a broad range of patients. Here, we studied the effects of HBO on the activity of neutrophils isolated from severely injured patients (days 1–2 after trauma), in fact on the production of reactive oxygen species (ROS) and release of neutrophil extracellular traps (NETs). We found exposure to HBO therapy to significantly diminish phorbol-12-myristate-13-acetate (PMA)-induced ROS production in neutrophils isolated from patients and healthy volunteers. At the same time, marked decrease in NETs release was found in control cells and a less pronounced reduction in patient neutrophils. Impaired ability to produce ROS following exposure to HBO was demonstrated to be linked to a strong downregulation of the activity of p38 MAPK. Only slight suppression of ERK activity could be found. In addition, HBO did not influence neutrophil chemotaxis or apoptosis, respectively. Collectively, this study shows for the first time that HBO therapy suppresses ROS production in inflammatory human neutrophils, and thus might impair ROS-dependent pathways, e.g. kinases activation and NETs release. Thus, HBO might represent a feasible therapy for patients suffering from systemic inflammation, including those with multiple trauma.

Highlights

Severe inflammation induced by major trauma and ischemia-reperfusion injury increases the risk of development complications such as sepsis, acute respiratory distress syndrome (ARDS) and organ failure [1]
Hyperbaric oxygen (HBO) reduces reactive oxygen species (ROS) production and neutrophil extracellular traps (NETs) release from inflammatory neutrophils Effective neutrophil activation is important for a successful host defense but in severe systemic inflammation elicited by trauma or sepsis, these cells contribute to collateral tissue damage
That ROS are critically involved in NETosis and neutrophils displaying mutations in the NADPH oxidase are unable to form NETs, we further quantified NETs levels

Summary

Introduction

Severe inflammation induced by major trauma and ischemia-reperfusion injury increases the risk of development complications such as sepsis, acute respiratory distress syndrome (ARDS) and organ failure [1]. Neutrophils can counteract invading pathogens by directly phagocytosing microbes or releasing cytotoxic molecules by degranulation, including ROS, proteases, collagenases, and myeloperoxidase (MPO) [6] In sterile inflammation, such as trauma, neutrophils are known to produce elevated levels of spontaneous ROS and uncontrolled release of aggressive oxygen molecules contributes to vascular leakage, predisposing patients to organ injury. The requirement for ROS production is consistent with the findings that neutrophils treated with the pharmacological NADPH-oxidase inhibitor diphenyleneiodonium (DPI) and patients with defective NADPH-oxidase are unable to release NETs [15] Apart from their antimicrobial function, uncontrolled NETs release following, sepsis, trauma and ischemia-reperfusion injury can contribute to tissue destruction by damaging epithelial and endothelial cells [16]. Previous studies have reported that NETs may predict posttraumatic complications in the intensive care setting and NETs levels have been demonstrated to be elevated in trauma patients who subsequently developed sepsis [17, 18]

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