Abstract
Current biomarkers for sepsis are limited by their non-specificity, short half-life, and insensitive response to therapy. Recently, we have demonstrated that citrullinated histone H3(CitH3) is released into the blood from neutrophil extracellular traps(NETs) in response to severe infection, and CitH3 may be a potential biomarker for sepsis. In the present study, we found that NET components were released in mouse models of both lipopolysaccharide(LPS)-induced shock (LPSS) and hemorrhagic shock (HS). To further quantify CitH3 in the NETs, we established a CitH3 specific enzyme-linked immunosorbent assay. Circulating CitH3 was found to be elevated only in LPSS but not in HS. Importantly, blood CitH3 was detected 30 minutes after LPS insult, and remained elevated for 24 hours (period of the highest mortality). Treatment of endotoxic mice with YW3-56, a peptidylarginine deiminase-2/4 inhibitor, significantly diminished levels of CitH3 in the blood. Interleukin-1β did not respond to LPS early, and interleukin-1β and interleukin-6 fluctuated although they responded to treatment. Procalcitonin reacted to LPS insult late. Compared to CitH3, these biomarkers were non-specifically induced in LPSS and HS. Collectively, our results demonstrate that YW3-56 protects animals from LPSS, and CitH3 is a reliable biomarker due to its early appearance, specificity, duration, and response to therapeutic intervention.
Highlights
Sepsis is a leading cause of death in the intensive care units[1]
We have previously demonstrated that neutrophil extracellular trap (NET) are the source of circulating citrullination of histone H3 (CitH3) in mouse model of LPSS13
Circulating CitH3 was significantly increased after LPS injection (Fig. 1B) (1.18 ± 0.3 ng/ml vs 0 ± 0 ng/ ml, p = 0.0025) while the CitH3 was un-detectable after hemorrhagic shock (HS) (Fig. 1D)
Summary
Sepsis is a leading cause of death in the intensive care units[1]. Based on the latest consensus, sepsis is defined as life-threatening organ dysfunction induced by a dysregulated host response to infection[2]. It has been suggested that an ideal septic biomarker should have the following characteristics[15,16,17,18]: (1) short time of induction after a bacterial stimulus, (2) specificity (e.g., positive for sepsis and negative for non-infectious inflammation), and (3) long half-life (to be detected in circulation). It remains to be determined whether CitH3 possesses these characteristics, and whether it is responsive to therapeutic intervention. We intended to assess advantages of CitH3 as a reliable specific biomarker for endotoxic shock, compared to PCT, IL-1β, and IL-6 in both mouse models of LPSS and hemorrhagic shock (HS)
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