Zhang Yuanyuan, Zhang Jia, Ren Yifan, Li Teng, Bi Jianbin, Du Zhaoqing, Wu Rongqian
Department of Pediatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
Shock. 2021 Feb 1;55(2):268-273. doi: 10.1097/SHK.0000000000001624.
Neonatal sepsis is a life-threatening inflammatory condition. Extracellular cold-inducible RNA-binding protein (CIRP), a proinflammatory mediator, plays a critical role in the pathogenesis of sepsis-induced lung injury in neonates. Luteolin, a polyphenolic flavonoid, has potent anti-inflammatory properties. However, the effects of luteolin on CIRP production and neonatal sepsis-induced lung injury remained unknown. We therefore hypothesize that treatment with luteolin suppresses CIRP production and attenuates lung injury in neonatal sepsis. To study this, sepsis was induced in C57BL/6J mouse pups (5-7 days) by intraperitoneal cecal slurry injection (CSI). One hour after CSI, luteolin (10 mg/kg body weight) or vehicle (normal saline) was administered through intraperitoneal injection. CIRP mRNA and protein were determined and lung injury was assessed at 10 h after CSI. Our results showed that administration of luteolin decreased CIRP mRNA and protein, improved lung architecture, reduced lung edema, and apoptosis after CSI. To examine the direct effect of luteolin on CIRP production, peritoneal macrophages were isolated from neonatal mice and stimulated with 100 ng/mL LPS with or without the presence of luteolin. The result indicates that luteolin directly inhibited LPS-induced CIRP production in neonatal macrophages. In addition, luteolin also downregulated hypoxia-inducible factor-1α (HIF-1α) and NOD-like receptor 3 (NLRP3) expression in septic neonates and in LPS-stimulated neonatal macrophages. In conclusion, administration of luteolin suppresses CIRP production and attenuates lung injury in neonatal sepsis. The beneficial effect of luteolin may be related to downregulation of HIF-1α and NLRP3 expression in neonatal macrophages. Luteolin may be developed as an adjunctive therapy for neonatal sepsis.
新生儿败血症是一种危及生命的炎症性疾病。细胞外冷诱导RNA结合蛋白（CIRP）作为一种促炎介质，在新生儿败血症诱导的肺损伤发病机制中起关键作用。木犀草素是一种多酚类黄酮，具有强大的抗炎特性。然而，木犀草素对CIRP产生及新生儿败血症诱导的肺损伤的影响尚不清楚。因此，我们推测木犀草素治疗可抑制CIRP产生并减轻新生儿败血症中的肺损伤。为研究此问题，通过腹腔注射盲肠匀浆（CSI）在C57BL/6J幼鼠（5 - 7日龄）中诱导败血症。CSI后1小时，通过腹腔注射给予木犀草素（10毫克/千克体重）或溶剂（生理盐水）。在CSI后10小时测定CIRP mRNA和蛋白，并评估肺损伤情况。我们的结果显示，给予木犀草素可降低CIRP mRNA和蛋白水平，改善肺结构，减轻肺水肿及细胞凋亡。为检验木犀草素对CIRP产生的直接作用，从新生小鼠中分离腹腔巨噬细胞，并用100纳克/毫升脂多糖（LPS）刺激，同时或不添加木犀草素。结果表明，木犀草素可直接抑制新生巨噬细胞中LPS诱导的CIRP产生。此外，木犀草素还下调败血症新生儿及LPS刺激的新生巨噬细胞中缺氧诱导因子-1α（HIF-1α）和NOD样受体3（NLRP3）的表达。总之，给予木犀草素可抑制CIRP产生并减轻新生儿败血症中的肺损伤。木犀草素的有益作用可能与下调新生巨噬细胞中HIF-1α和NLRP3的表达有关。木犀草素可能被开发为新生儿败血症的辅助治疗药物。
