Duan Zehua, Xie Tian, Chu Chengnan, Chen Fang, Wang Xinyu, Li Jieshou, Ding Weiwei
Division of Trauma and Surgical Intensive Care Unit, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu Province, PR China.
Department of Hepatobiliary and Pancreatic Surgery, Union Shenzhen Hospital, Huazhong University of Science and Technology, Shenzhen, 518000, Guangdong Province, PR China.
Cell Death Discov. 2021 Nov 10;7(1):345. doi: 10.1038/s41420-021-00745-0.
Empiric broad-spectrum antimicrobials therapy is suggested to be started immediately for sepsis patients. Empiric antimicrobial therapy should be narrowed once pathogen identification and sensitivities are established. However, the detailed mechanisms of de-escalation strategy are still unclear. Here we hypothesized neutrophil extracellular traps (NETs) played an essential role and de-escalation strategy might alleviate organs injury through regulation of NETs formation in sepsis. We evaluated the effect of imipenem and ceftriaxone on NETs formation in vitro and examined the role of reactive oxygen species (ROS). Next, we designed de-escalation and escalation strategy in cecum ligation and puncture (CLP) models. Organ injury, inflammatory cytokines, NETs levels were compared and evaluated. In CLP models, de-escalation therapy resulted in an increased serum MPO-DNA level during the early stage and decreased MPO-DNA level during late stage, which exerted the reverse effects in escalation therapy. Inflammatory response and organ injury exacerbated when eliminated NETs with DNAse I during the early stage of sepsis (p < 0.01). Histopathological analysis showed decreased injury in lung, liver, and intestine in de-escalation therapy compared with escalation therapy (p < 0.01). De-escalation therapy results in the highest 6-day survival rate compared with the control group (p < 0.01), however, no significant difference was found between de-escalation and escalation group (p = 0.051). The in vitro study showed that the imipenem could promote, while the ceftriaxone could inhibit the formation of NETs in PMA-activated PMNs through a ROS-dependent manner. We firstly demonstrate that de-escalation, not escalation, therapy reduces organ injury, decreases inflammatory response by promoting NETs formation in the early stage, and inhibiting NETs formation in the late stage of sepsis.
建议对脓毒症患者立即开始经验性广谱抗菌治疗。一旦确定病原体及其敏感性，经验性抗菌治疗应予以调整。然而，降阶梯策略的具体机制仍不清楚。在此，我们假设中性粒细胞胞外陷阱（NETs）起关键作用，且降阶梯策略可能通过调节脓毒症中NETs的形成来减轻器官损伤。我们评估了亚胺培南和头孢曲松对体外NETs形成的影响，并研究了活性氧（ROS）的作用。接下来，我们在盲肠结扎和穿刺（CLP）模型中设计了降阶梯和升阶梯策略。比较并评估了器官损伤、炎性细胞因子及NETs水平。在CLP模型中，降阶梯治疗在早期导致血清髓过氧化物酶 - DNA（MPO - DNA）水平升高，而在后期降低，升阶梯治疗则产生相反效果。在脓毒症早期用脱氧核糖核酸酶I消除NETs时，炎症反应和器官损伤加剧（p < 0.01）。组织病理学分析显示，与升阶梯治疗相比，降阶梯治疗导致肺、肝和肠道的损伤减轻（p < 0.01）。与对照组相比，降阶梯治疗的6天生存率最高（p < 0.01），然而，降阶梯组与升阶梯组之间未发现显著差异（p = 0.051）。体外研究表明，亚胺培南可促进，而头孢曲松可通过依赖ROS的方式抑制PMA激活的中性粒细胞中NETs的形成。我们首次证明，降阶梯治疗而非升阶梯治疗可减轻器官损伤，通过在脓毒症早期促进NETs形成及在后期抑制NETs形成来降低炎症反应。
