Abstract
ObjectivesSeptic syndromes are the leading cause of death in intensive care units. They are characterized by the development of immune dysfunctions such as endotoxin tolerance (ET), whose intensity and duration are associated with increased risk of nosocomial infections and mortality. Alarmins S100A8 and S100A9 have been shown to be increased after septic shock. Importantly, a delayed S100A9 mRNA increase predicts hospital-acquired infection in patients. The aim of this study was to investigate the regulation of S100A8 and S100A9 mRNA expression in an ex vivo model of ET.Subjects and MeasurementsET was reproduced ex vivo by priming healthy peripheral blood mononuclear cells (number of donors = 9 to 10) with low-dose endotoxin (2 ng/ml) before stimulation with high dose endotoxin (100 ng/ml). S100A8 and S100A9 mRNA levels were measured by quantitative real-time polymerase chain reactions.Main ResultsET was established by observing decreased TNFα and increased IL-10 transcriptomic responses to two subsequent endotoxin challenges. Interestingly, ET was associated with increased S100A8 and S100A9 mRNA expression ex vivo. We showed that IL-10 played a role in this process, since S100A8 and S100A9 mRNA increases were significantly abrogated by IL-10 blockade in the model. Conversely, treatment with rIFN-γ, a pro-inflammatory and immunostimulating molecule known to block ET induction, was able to restore normal S100A8 and S100A9 mRNA in this model.ConclusionsIn this ex vivo model, we observed that S100A8 and S100A9 mRNA expression was significantly increased during ET. This reproduced ex vivo the observations we had previously made in septic shock patients. Interestingly, IL-10 blockade and rIFN-γ treatment partially abrogated S100A8/A9 mRNA increases in this model. Pending confirmation in larger, independent clinical studies, these preliminary results suggest that S100A8 and S100A9 mRNA levels might be used as surrogate markers of ET and as stratification tools for personalized immunotherapy in septic shock patients.
Highlights
Sepsis is a major health care challenge and represents one of the leading causes of death in intensive care units
We showed that IL-10 played a role in this process, since S100A8 and S100A9 messenger RNA (mRNA) increases were significantly abrogated by IL-10 blockade in the model
In this ex vivo model, we observed that S100A8 and S100A9 mRNA expression was significantly increased during endotoxin tolerance (ET)
Summary
Sepsis is a major health care challenge and represents one of the leading causes of death in intensive care units. It affects 750,000 people annually in the United States, and its incidence is increasing, partially because of the aging population. In septic shock patients who survive the initial inflammatory storm, the immune response often evolves toward a state of immunosuppression, which contributes to increased mortality and severe secondary hospital-acquired infections [2,3]. One of the current trends in the therapeutic management of sepsis is treatment of this immune dysfunction in an attempt to improve the patient prognosis. A better understanding of the pathophysiology of sepsis-induced immune dysfunctions is mandatory for the development of these tests and new treatments
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