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凌林, 佟晶, 曾良. 芍药苷通过激活Nrf2/Keap1信号通路改善脓毒症急性肺损伤的研究[J]. koko体育app 学报（医学版）, 2020, 51(5): 664-669. DOI:
引用本文: 凌林, 佟晶, 曾良. 芍药苷通过激活Nrf2/Keap1信号通路改善脓毒症急性肺损伤的研究[J]. koko体育app 学报（医学版）, 2020, 51(5): 664-669. DOI:
LING Lin, TONG Jing, ZENG Liang. Paeoniflorin Improves Acute Lung Injury in Sepsis by Activating Nrf2/Keap1 Signaling Pathway[J]. Journal of Sichuan University (Medical Sciences), 2020, 51(5): 664-669. DOI:
Citation: ✤ LING Lin, TONG Jing, ZENG Liang. Paeoniflorin Improves Acute Lung Injury in Sepsis by Activating Nrf2/Keap1 Signaling Pathway[J]. Journal of Sichuan University (Medical Sciences), 2020, 51(5): 664-669. DOI:

芍药苷通过激活Nrf2/Keap1信号通路改善脓毒症急性肺损伤的研究

Paeoniflorin Improves Acute Lung Injury in Sepsis by Activating Nrf2/Keap1 Signaling Pathway

  • 摘要:
      目的  探讨芍药苷（paeoniflorin, PF）对脓毒症所致急性肺损伤的影响及其与转录因子NF-E2相关因子2（nuclear factor erythyroid 2-related factor 2, Nrf2）/Kelch样环氧氯丙烷相关蛋白-1（Keap1）信号通路的关系。
      方法  采用盲肠结扎穿孔（CLP）术诱导建立脓毒症大鼠模型。将大鼠随机分成假手术组（Sham）、模型组（Model）、低剂量PF组（L-PF，50 mg/kg）、高剂量PF组（H-PF，150 mg/kg）及高剂量PF+Nrf2抑制剂组（H-PF+ML385，150 mg/kg PF+30 mg/kg ML385），每组10只。采用改良的脓毒症严重程度评分标准对大鼠脓毒症严重程度进行评分；HE染色观察大鼠肺组织病理变化；黄嘌呤氧化酶法测定大鼠肺组织超氧化物歧化酶（SOD）活性；硫代巴比妥酸法测定大鼠肺组织丙二醛（MDA）含量；ELISA法检测肺组织中肿瘤坏死因子-α（TNF-α），白介素（IL）-1β和IL-6水平；Western blot和qRT-PCR分别检测肺组织中Nrf2、Keap1、血红素氧合酶1（HO-1）蛋白和mRNA的表达水平。
      结果  与Sham组比较，Model组大鼠出现严重的脓毒症；肺组织出现严重炎症浸润，出现大量巨噬细胞，肺间质肿大；肺组织中促炎因子IL-1β、TNF-α、IL-6及氧化指标MDA含量均上升（P<0.05），而抗氧化指标SOD含量下降（P<0.05）；Nrf2及HO-1蛋白和mRNA表达均降低（P<0.05），Keap1蛋白和mRNA表达增加（P<0.05）。与Model组比较，PF给药组大鼠脓毒症程度均降低，肺组织损伤均得到改善，肺组织中IL-1β、TNF-α、IL-6及MDA含量均下降（P<0.05），SOD活性均增加（P<0.05）；Nrf2及HO-1蛋白和mRNA表达均增加（P<0.05），Keap1蛋白和mRNA表达降低（P<0.05）。与H-PF组比较，Nrf2抑制剂ML385干预后可抑制PF对脓毒症大鼠上述指标的改善。
      结论  PF通过激活Nrf2/Keap1信号通路，降低组织氧化应激与炎症水平，改善脓毒症所致的急性肺损伤。
     
    Abstract:
      Objective  To investigate the effect of paeoniflorin (PF) on sepsis-induced acute lung injury and its relationship with nuclear factor erythyroid 2-related factor 2 (Nrf2)/Kelch-like ECH2 associated protein 1 (Keap1) signaling pathway.
      Methods  Cecal ligation and puncture (CLP) was used to induce the sepsis rat model. Rats were randomly divided into 5 groups (n=10): sham group (Sham), model group (Model), low dose PF group (L-PF group, 50 mg/kg PF), high dose PF group (H-PF group, 150 mg/kg PF) and high dose PF+Nrf2 inhibitor group (H-PF+ML385 group, 150 mg/kg PF+30 mg/kg ML385). The severity of sepsis in rats was scored according to the improved severity scale of sepsis; the pathological changes of lung tissue were observed by HE staining; the activity of superoxide dismutase (SOD) in lung tissue was determined by xanthine oxidase method; the content of malondialdehyde (MDA) in lung tissue was measured by thiobarbituric acid method; and the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in lung tissues were detected by ELISA. Western blot was used to detect the expression of Nrf2, Keap1 and HO-1 proteins in lung tissues.
      Results  Compared with Sham group, the sepsis symptoms in Model group were more serious, severe inflammatory infiltration in lung tissue, macrophages and interstitial enlargement, and the contents of pro-inflammatory factors IL-1β, TNF-α, IL-6 and oxidative index MDA in lung tissues were significantly increased (P<0.05), while the activity of antioxidant index SOD were significantly decreased (P<0.05). The protein and mRNA expression levels of Nrf2 and HO-1 were significantly decreased (P<0.05), while the protein and mRNA expression levels of Keap1 were markedly increased (P<0.05). Compared with the Model group, the severity of sepsis in PF groups was decreased, the lung tissue injury was improved, the contents of IL-1β, TNF-α, IL-6 and MDA in lung tissue were significantly decreased (P<0.05), the activity of SOD was markedly increased (P<0.05), the protein and mRNA expression levels of Nrf2 and HO-1 were significantly increased (P<0.05), and the expression levels of Keap1 protein and mRNA were significantly decreased (P<0.05). Compared with the H-PF group, Nrf2 inhibitor ML385 significantly inhibited the improvement of PF on lung injury in sepsis rats.
      Conclusion  PF can reduce oxidative stress and inflammation by activating Nrf2/Keap1 signaling pathway, and improve sepsis-induced acute lung injury.
     
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