Abstract
Cold-inducible RNA-binding protein (CIRP) is a novel sepsis inflammatory mediator and C23 is a putative CIRP competitive inhibitor. Therefore, we hypothesized that C23 can ameliorate sepsis-associated injury to the lungs and kidneys. First, we confirmed that C23 dose-dependently inhibited TNF-α release, IκBα degradation, and NF-κB nuclear translocation in macrophages stimulated with CIRP. Next, we observed that male C57BL/6 mice treated with C23 (8 mg/kg BW) at 2 h after cecal ligation and puncture (CLP) had lower serum levels of LDH, ALT, IL-6, TNF-α, and IL-1β (reduced by ≥39%) at 20 h after CLP compared with mice treated with vehicle. C23-treated mice also had improved lung histology, less TUNEL-positive cells, lower serum levels of creatinine (34%) and BUN (26%), and lower kidney expression of NGAL (50%) and KIM-1 (86%). C23-treated mice also had reduced lung and kidney levels of IL-6, TNF-α, and IL-1β. E-selectin and ICAM-1 mRNA was significantly lower in C23-treated mice. The 10-day survival after CLP of vehicle-treated mice was 55%, while that of C23-treated mice was 85%. In summary, C23 decreased systemic, lung, and kidney injury and inflammation, and improved the survival rate after CLP, suggesting that it may be developed as a new treatment for sepsis.
Highlights
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection[1,2,3]
These results demonstrate that C23 inhibits Cold-inducible RNA-binding protein (CIRP) activation of macrophages resulting in reduced IκBα degradation, decreased NF-κB nuclear translocation, and decreased tumor necrosis factor α (TNF-α) release
We have shown that CIRP promotes apoptosis in the lungs of mice with sepsis[13,20]
Summary
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection[1,2,3]. The septic stress disrupts crucial cellular and tissue functions, and exacerbates endoplasmic reticulum stress and leads to the release of damage-associated molecular pattern (DAMP) molecules and inflammatory mediators, which cause leukocyte and vascular endothelial cell (EC) activation, increased capillary permeability, neutrophil infiltration, and tissue injury[12,13]. CIRP acts as a damage-associated molecular pattern molecule (DAMP) to increase sepsis severity and mortality rate[18,19]. We have shown that CIRP plays a key role in acute kidney injury (AKI) after renal ischemia and reperfusion[22] These observations suggest CIRP may be a critical mediator for the development of sepsis-associated organ injury. In this study, we sought to determine the effects of C23 on inflammation and tissue injury in a mouse model of abdominal polymicrobial sepsis
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