Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY, 11030, United States.
Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, 11030, United States.
Sci Rep. 2018 Feb 12;8(1):3052. doi: 10.1038/s41598-017-13139-z.
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.
冷诱导 RNA 结合蛋白 (CIRP) 是一种新型的脓毒症炎症介质，C23 是一种假定的 CIRP 竞争性抑制剂。因此，我们假设 C23 可以改善脓毒症相关的肺和肾损伤。首先，我们证实 C23 能够剂量依赖性地抑制 CIRP 刺激的巨噬细胞中 TNF-α 的释放、IκBα 的降解和 NF-κB 的核易位。接下来，我们观察到，在盲肠结扎和穿刺 (CLP) 后 2 小时给予 C23 (8mg/kgBW) 的雄性 C57BL/6 小鼠，在 CLP 后 20 小时时血清中 LDH、ALT、IL-6、TNF-α 和 IL-1β 的水平降低了≥39%（与给予载体的小鼠相比）。C23 治疗的小鼠肺组织学也得到改善，TUNEL 阳性细胞减少，血清肌酐（34%）和 BUN（26%）水平降低，肾脏 NGAL（50%）和 KIM-1（86%）的表达降低。C23 治疗的小鼠还降低了肺和肾组织中 IL-6、TNF-α 和 IL-1β 的水平。C23 治疗的小鼠中 E-选择素和 ICAM-1 的 mRNA 水平也显著降低。给予载体的小鼠在 CLP 后的 10 天生存率为 55%，而给予 C23 的小鼠的生存率为 85%。综上所述，C23 降低了全身、肺和肾损伤和炎症，并提高了 CLP 后的生存率，这表明它可能被开发为脓毒症的一种新治疗方法。
