Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang 150001, China.
Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, China.
Int Immunopharmacol. 2021 Jun;95:107529. doi: 10.1016/j.intimp.2021.107529. Epub 2021 Mar 18.
Sepsis is a systemic inflammatory response syndrome resulted from severe infection. Excessive inflammation response plays an important role in sepsis-induced acute lung injury (ALI). Loganin is an iridoid glycoside isolated from Corni fructus and exerts an anti-inflammatory effect in multiple inflammatory diseases; however, the role of loganin in sepsis-induced ALI remains unknown. In the current study, the cecal ligation and puncture (CLP)-induced murine sepsis model was constructed to investigate the anti-inflammatory property of loganin in sepsis-induced ALI. Lipopolysaccharide (LPS)-treated Raw 264.7 cells and primary murine peritoneal macrophages were established to further explore underlying mechanism of loganin. Results showed that intragastrical administration of loganin significantly increased murine survival, reduced the alveolar structure damage and inflammatory cell infiltration. Loganin suppressed the release of the M1 macrophage-associated pro-inflammatory cytokines and induced the activation of M2-type anti-inflammatory cytokines. Besides, loganin dramatically inhibited NLRP3 inflammasome-mediated caspase-1 activation and subsequent IL-1β secretion. Further in vitro studies confirmed that loganin efficiently inhibited M1 macrophage polarization and NLRP3 inflammasome activation by blocking the extra-cellular signal-regulated kinase (ERK) and nuclear factor-kappa B (NF-κB) pathways. Taken together, the anti-inflammatory effect of loganin in sepsis-induced ALI was associated with the ERK and NF-κB pathway-mediated macrophage polarization and NLRP3 inflammasome activation. Our study offers a favorable mechanistic basis to support the therapeutic potential of loganin in anti-inflammatory diseases, such as sepsis-induced ALI.
脓毒症是由严重感染引起的全身炎症反应综合征。过度的炎症反应在脓毒症引起的急性肺损伤（ALI）中起重要作用。栀子苷是从山茱萸果实中分离得到的环烯醚萜苷，在多种炎症性疾病中具有抗炎作用；然而，栀子苷在脓毒症引起的 ALI 中的作用尚不清楚。在本研究中，构建了盲肠结扎和穿刺（CLP）诱导的小鼠脓毒症模型，以研究栀子苷在脓毒症诱导的 ALI 中的抗炎作用。建立了脂多糖（LPS）处理的 Raw 264.7 细胞和原代小鼠腹腔巨噬细胞，进一步探讨了栀子苷的作用机制。结果表明，腹腔内给予栀子苷可显著提高小鼠的存活率，减轻肺泡结构损伤和炎性细胞浸润。栀子苷抑制 M1 型巨噬细胞相关促炎细胞因子的释放，并诱导 M2 型抗炎细胞因子的激活。此外，栀子苷可显著抑制 NLRP3 炎性体介导致炎细胞因子-1β（IL-1β）的分泌。进一步的体外研究证实，栀子苷通过阻断细胞外信号调节激酶（ERK）和核因子-κB（NF-κB）通路，有效抑制 M1 型巨噬细胞极化和 NLRP3 炎性体的激活。综上所述，栀子苷在脓毒症诱导的 ALI 中的抗炎作用与 ERK 和 NF-κB 通路介导的巨噬细胞极化和 NLRP3 炎性体激活有关。本研究为栀子苷在抗炎性疾病（如脓毒症诱导的 ALI）中的治疗潜力提供了有利的机制基础。
