Serum citrullinated histone H3 concentrations differentiate patients with septic verses non-septic shock and correlate with disease severity

Abstract

Purpose Microbial infection stimulates neutrophil/macrophage/monocyte extracellular trap formation, which leads to the release of citrullinated histone H3 (CitH3) catalyzed by peptidylarginine deiminase (PAD) 2 and 4. Understanding these molecular mechanisms in the pathogenesis of septic shock will be an important next step for developing novel diagnostic and treatment modalities. We sought to determine the expression of CitH3 in patients with septic shock, and to correlate CitH3 levels with PAD2/PAD4 and clinically relevant outcomes. Methods Levels of CitH3 were measured in serum samples of 160 critically ill patients with septic and non-septic shock, and healthy volunteers. Analyses of clinical and laboratory characteristics of patients were conducted. Results Levels of circulating CitH3 at enrollment were significantly increased in septic shock patients (n = 102) compared to patients hospitalized with non-infectious shock (NIC) (n = 32, p < 0.0001). The area under the curve (95% CI) for distinguishing septic shock from NIC using CitH3 was 0.76 (0.65–0.86). CitH3 was positively correlated with PAD2 and PAD4 concentrations and Sequential Organ Failure Assessment Scores [total score (r = 0.36, p < 0.0001)]. The serum levels of CitH3 at 24 h (p < 0.01) and 48 h (p < 0.05) were significantly higher in the septic patients that did not survive. Conclusion CitH3 is increased in patients with septic shock. Its serum concentrations correlate with disease severity and prognosis, which may yield vital insights into the pathophysiology of sepsis.

Kynurenic Acid and Its Synthetic Derivatives Protect Against Sepsis-Associated Neutrophil Activation and Brain Mitochondrial Dysfunction in Rats

“…Among these, CitH3 is highly specific to NET formation, and it was also suggested as a therapeutic target in experimental models of sepsis ( 38 , 39 ). CitH3, together with its generating enzymes, peptidylarginine deiminases, was implicated in accelerating thrombotic processes ( 40 ), and their levels correlated with SOFA scores, disease severity and ICU mortality in septic shock patients ( 41 , 42 ). In our study, apart from elevations in CitH3 plasma levels, plasma levels of the NET-inducer IL-1β and the neutrophil-derived MPO in plasma and brain tissues were also markedly increased in septic rats.…”

The Immune System Throws Its Traps: Cells and Their Extracellular Traps in Disease and Protection

“…This is likely to depend on the model of infection or inflammatory disease. This knowledge may be used in new therapeutic or diagnosis/prognosis strategies, as described by Tian et al, who detected CitH3 in the serum of patients with septic shock, and could associate the levels of this compound with the severity and the prognosis of the disease [153].…”

Peptidylarginine Deiminase 2 in Host Immunity: Current Insights and Perspectives

“…Since lactate and PCT are considered markers for the prognosis and the severity of sepsis (109,110), elevated PAD2 levels in serum may also serve as a future clinical biomarker and predictor of outcomes. Circulating CitH3 was also found to be positively correlated with blood PAD2 (r values=0.0452, p<0.001) and PAD4 levels (r value=0.363, p<0.01), respectively (108). The levels of PAD2 in bronchoalveolar lavage fluid (BALF) from patients with sepsis and respiratory distress syndrome (ARDS) are also significantly increased compared with those in a healthy control group (108).…”