Abstract
Sepsis is generally considered as a severe condition of inflammation that leads to lymphocyte apoptosis and multiple organ dysfunction. Hydroxysafflor yellow A (HSYA) exerts anti-inflammatory and anti-apoptotic effects in infectious diseases. However, the therapeutic effect of HSYA on polymicrobial sepsis remains unknown. This study was undertaken to investigate the therapeutic effects and the mechanisms of action of HSYA on immunosuppression in a murine model of sepsis induced by cecal ligation and puncture (CLP). NIH mice were randomly divided into four groups: control group, sham group, CLP group, and CLP+HSYA group. HSYA (120 mg/kg) was intravenously injected into experimental mice at 12 h before CLP, concurrent with CLP and 12 h after CLP. The levels of circulating inflammatory cytokines, the apoptosis of CD4+ and CD8+ T lymphocytes, and protein expression of cytochrome C (Cytc), Bax, Bcl-2, cleaved caspase-9, and cleaved caspase-3 were examined. Plasma levels of IL-6, IL-10 and TNF-alpha as well as the apoptosis of CD4+ T lymphocytes were increased compared with sham group. These changes were accompanied by increases of pro-apoptotic proteins including Cytc, Bax, cleaved caspase-9, and cleaved caspase-3 and decreases of anti-apoptotic protein Bcl-2 in CD4+ T lymphocytes from mice undergoing CLP. In contrast, we fail to observe significant effect of HSYA on the apoptosis of CD8+ T lymphocytes in CLP-treated group. Of note, HSYA treatment reversed all above changes observed in CD4+ T lymphocytes, and significantly increased the ratio of CD4+:CD8+ T lymphocytes in CLP-treated mice. In conclusion, HSYA was an effective therapeutic agent in ameliorating sepsis-induced apoptosis of CD4+ T lymphocytes probably through its anti-inflammatory and anti-apoptotic effects.
Highlights
Sepsis is a life-threatening condition caused by dysregulated host response to infection (Singer et al, 2016; Thompson et al, 2017), and has been recognized as one of the most significant causes for mortality worldwide (Fullerton et al, 2017; Gunes Ozaydin et al, 2017)
To define the optimal dosage of Hydroxysafflor yellow A (HSYA) to be used in this study, we conducted a preliminary experiment and tested three different dosages in mice that were subjected to cecal ligation and puncture (CLP) operation: 60, 120, and 180 mg/kg
Our preliminary data showed that compared with the CLP group, the lymphocyte counts and the serum levels of inflammatory cytokines of HSYAtreated mice were significantly improved with a daily dosage of 120 mg/kg or higher (Supplementary Figure 1 and Table 2)
Summary
Sepsis is a life-threatening condition caused by dysregulated host response to infection (Singer et al, 2016; Thompson et al, 2017), and has been recognized as one of the most significant causes for mortality worldwide (Fullerton et al, 2017; Gunes Ozaydin et al, 2017). The pathophysiology of sepsis is characterized by marked immunosuppression (Boomer et al, 2011), and immune cell apoptosis is thought to be a major contributor to this immunosuppressive status under septic conditions (Chen H.M. et al, 2016; Sonego et al, 2016). Emerging evidence suggests that peripheral CD4+ T lymphocytes undergo apoptosis in response to septic conditions, leading to marked decreases in numbers of CD4+ T lymphocytes (Cabrera-Perez et al, 2014; Gao et al, 2016). Therapies that prevent immune cell apoptosis could significantly reduce the mortality rate of sepsis (Oberholzer et al, 2001). Agents that protect mitochondria dysfunction may improve the clinical outcomes of septic patients
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