Han Sang Hoon, Kim Jin Seok, Woo Jun Hee, Jeong Su Jin, Shin Jeon Soo, Ahn Young Soo, Kim June Myung
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Yonsei Med J. 2015 Jan;56(1):112-23. doi: 10.3349/ymj.2015.56.1.112.
Although the proteasome inhibitor known as bortezomib can modulate the inflammatory process through the nuclear factor-kappa B signaling pathway, the immunomodulatory effect of pre-incubated bortezomib has not been fully evaluated for inflammation by infectious agents. Therefore, we evaluated the effect of bortezomib on the expression of inflammatory cytokines and mediators in macrophage cell lines and on survival in a murine peritonitis sepsis model.
Bortezomib was applied 1 hr before lipopolysaccharide (LPS) stimulation in RAW 264.7 cells. The cecal ligation and puncture (CLP) experiments were performed in C57BL/6J mice.
Pre-incubation with bortezomib (25 nM or 50 nM) prior to LPS (50 ng/mL or 100 ng/mL) stimulation significantly recovered the number of viable RAW 264.7 cells compared to those samples without pre-incubation. Bortezomib decreased various inflammatory cytokines as well as nitric oxide production in LPS-stimulated cells. The 7-day survival rate in mice that had received bortezomib at 0.01 mg/kg concentration 1 hr prior to CLP was significantly higher than in the mice that had only received a normal saline solution of 1 mL 1 hr prior to CLP. In addition, the administration of bortezomib at 0.01 mg/kg concentration 1 hr before CLP resulted in a significant decrease in inflammation of the lung parenchyma. Collectively, pretreatment with bortezomib showed an increase in the survival rate and changes in the levels of inflammatory mediators.
These results support the possibility of pretreatment with bortezomib as a new therapeutic target for the treatment of overwhelming inflammation, which is a characteristic of severe sepsis.
虽然名为硼替佐米的蛋白酶体抑制剂可通过核因子-κB信号通路调节炎症过程，但预先孵育的硼替佐米对感染因子所致炎症的免疫调节作用尚未得到充分评估。因此，我们评估了硼替佐米对巨噬细胞系中炎性细胞因子和介质表达的影响以及对小鼠腹膜炎脓毒症模型生存率的影响。
在RAW 264.7细胞中，于脂多糖（LPS）刺激前1小时应用硼替佐米。在C57BL/6J小鼠中进行盲肠结扎和穿刺（CLP）实验。
与未预先孵育的样本相比，在LPS（50 ng/mL或100 ng/mL）刺激前预先用硼替佐米（25 nM或50 nM）孵育可显著恢复存活RAW 264.7细胞的数量。硼替佐米可降低LPS刺激细胞中多种炎性细胞因子以及一氧化氮的产生。在CLP前1小时接受0.01 mg/kg浓度硼替佐米的小鼠的7天生存率显著高于仅在CLP前1小时接受1 mL生理盐水的小鼠。此外，在CLP前1小时给予0.01 mg/kg浓度的硼替佐米可显著减轻肺实质的炎症。总体而言，硼替佐米预处理显示生存率提高以及炎性介质水平发生变化。
这些结果支持将硼替佐米预处理作为治疗严重脓毒症特征性的压倒性炎症的新治疗靶点的可能性。
