PDF(Pubmed)
Abstract：
The steady rise of sepsis globally has reached almost 49 million cases in 2017, and 11 million sepsis-related deaths. The genomic response to sepsis comprising multi-system stage of raging microbial inflammation has been reported in the whole blood, while effective treatment is lacking besides anti-microbial therapy and supportive measures. Here we show that, astoundingly, 6,237 significantly expressed genes in sepsis are increased or decreased in the lungs, the site of acute respiratory distress syndrome (ARDS). Moreover, 5,483 significantly expressed genes in sepsis are increased or decreased in the kidneys, the site of acute injury (AKI). This massive genomic response to polymicrobial sepsis is countered by the selective nuclear blockade with the cell-penetrating Nuclear Transport Checkpoint Inhibitor (NTCI). It controlled 3,735 sepsis-induced genes in the lungs and 1,951 sepsis-induced genes in the kidneys. The NTCI also reduced without antimicrobial therapy the bacterial dissemination: 18-fold in the blood, 11-fold in the lungs, and 9-fold in the spleen. This enhancement of bacterial clearance was not significant in the kidneys. Cumulatively, identification of the sepsis-responsive host\'s genes and their control by the selective nuclear blockade advances a better understanding of the multi-system mechanism of sepsis. Moreover, it spurs much-needed new diagnostic, therapeutic, and preventive approaches.
摘要：
2017年，全球败血症的稳步上升已达到近4900万病例，1100万败血症相关死亡。已经在全血中报道了对脓毒症的基因组反应，包括肆虐的微生物炎症的多系统阶段，除了抗微生物治疗和支持措施外，还缺乏有效的治疗方法。在这里我们展示，令人惊讶的是,6,237个在脓毒症中显著表达的基因在肺中增加或减少，急性呼吸窘迫综合征（ARDS）的部位。此外，5,483个在脓毒症中显著表达的基因在肾脏中增加或减少，急性损伤部位（AKI）。这种对多微生物败血症的大规模基因组反应被细胞穿透核转运检查点抑制剂（NTCI）的选择性核阻断所抵消。它控制了3,735个败血症诱导的肺部基因和1,951个败血症诱导的肾脏基因。NTCI在没有抗菌治疗的情况下也减少了细菌传播：血液中的18倍，肺部11倍，和9倍的脾脏。这种细菌清除的增强在肾脏中并不显著。累计,对败血症反应性宿主基因的鉴定及其通过选择性核阻断的控制促进了对败血症多系统机制的更好理解。此外，它刺激了急需的新诊断，治疗性的,和预防方法。
