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许宝胜, 刘洪涛, 冶国栋, 等. 基于Keap1/Nfr2/ARE信号通路研究呼吸机相关性肺损伤分子机制[J]. 四川大学学报（医学版）, 2019, 50(3): 317-322.
引用本文: 许宝胜, 刘洪涛, 冶国栋, 等. 基于Keap1/Nfr2/ARE信号通路研究呼吸机相关性肺损伤分子机制[J]. 四川大学学报（医学版）, 2019, 50(3): 317-322.
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XU Bao-sheng, LIU Hong-tao, YE Guo-dong, et al. Molecular Mechanism of Ventilator-associated Lung Injury Based on Keap1/Nfr2/ARE Signaling Pathway[J]. Journal of Sichuan University (Medical Sciences), 2019, 50(3): 317-322.
Citation: XU Bao-sheng, LIU Hong-tao, YE Guo-dong, et al. Molecular Mechanism of Ventilator-associated Lung Injury Based on Keap1/Nfr2/ARE Signaling Pathway[J]. Journal of Sichuan University (Medical Sciences), 2019, 50(3): 317-322.
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基于Keap1/Nfr2/ARE信号通路研究呼吸机相关性肺损伤分子机制

Molecular Mechanism of Ventilator-associated Lung Injury Based on Keap1/Nfr2/ARE Signaling Pathway

    摘要
  • 摘要:
      目的  探索基于Keap1/Nfr2/ARE信号通路探索呼吸机相关肺损伤（ventilation induced lung injury，VILI）形成的分子机制。
      方法  给予SD大鼠过度机械通气建造VILI模型；HE染色检测对照组、正常潮气量（VT）组（VT为8 mL/kg）、大VT组（VT为40 mL/kg）肺组织病理变化；检测各组肺组织湿重/干重（W/D）比值变化；BCA法检测各组支气管肺泡灌洗液（BALF）中总蛋白的变化；ELISA法检测各组BALF和血清中白细胞介素1β（IL-1β）、白细胞介素-8（IL-18）以及肺组织中8-羟基脱氧鸟苷（8-OHdG）的水平变化；TBA法检测肺组织中丙二醛（MDA）水平变化；Western bloting实验检测巨噬细胞中Nod样受体蛋白3(NLRP3)、凋亡相关斑点样蛋白(ASC)、caspase-1蛋白以及肺组织中Keap1、Nrf2蛋白的变化；逆转录PCR检测各组肺组织中SOD mRNA、HO-1 mRNA表达变化。
      结果  过度机械通气可损伤肺组织，导致肺泡破裂、炎症细胞浸润和红细胞增多；与对照组和正常VT组相比，大VT组肺组织W/D值、8-OHdG和MDA水平、BALF中总蛋白、IL-1β、IL-18以及血清中IL-1β、IL-18水平均显著上升（P均<0.05），肺泡巨噬细胞中NLRP3、ASC、caspase-1蛋白以及肺组织中Keap1蛋白表达上升（P均<0.05），肺组织中Nrf2蛋白、SOD mRNA、HO-1 mRNA表达下降。
      结论  大VT通气可以使肺组织发生急性炎症性损伤并导致VILI的发生，其机制为过度通气引起Keap1/Nrf2-ARE通路抑制和活性氧（ROS）清除能力的下降，进而引起肺巨噬细胞产生NLRP3炎症小体，参与VILI的形成。

     

    Abstract:
      Objective  To explore the molecular mechanism of ventilation induced lung injury (VILI) formation based on Keap1/Nfr2/ARE signaling pathway.
      Methods  The VILI model was established by excessive mechanical ventilation in SD rats. HE staining was used to detect the pathological changes of lung tissue in the control group, normal tidal volume (VT) group and large VT group (VT 40 mL/kg). The wet weight of lung tissue was detected in each group. Dry weight (W/D) ratio change; BCA method was used to detect the changes of total protein in bronchoalveolar lavage fluid (BALF) of each group; ELISA was used to detect interleukin-1β (IL-1β) and leukocyte in BALF and serum of each group. The content of 8-OHdG in the lung tissue was detected by IL-8 and the content of malondialdehyde (MDA) in the lung tissue was detected by TBA method. The NLRP3, ASC and caspase-1 proteins in macrophages were detected by Western blotting. The changes of Keap1 and Nrf2 proteins in lung tissues were detected by RT-PCR. The expressions of SOD mRNA and HO-1 mRNA in lung tissues of each group were detected by RT-PCR.
      Results  Excessive mechanical ventilation could damage lung tissue, leading to alveolar rupture, inflammatory cell infiltration and erythrocytosis. Compared with the control group and normal VT group, the W/D value, 8-OHdG and MDA content in the large VT group, and total BALF, the contents of IL-1β and IL-18 in protein, IL-1β, IL-18 in serum increased significantly (P<0.05). Compared with the control group and normal VT group, NLRP3, ASC, in macrophage of large VT group, the content of Keap1 protein in caspase-1 protein and lung tissue increased significantly (P<0.05). The expression of Nrf2 protein, SOD mRNA and HO-1 mRNA in lung tissue decreased significantly.
      Conclusions  Large VT ventilation can cause acute inflammatory injury in lung tissue and lead to the occurrence of VILI. Inflammatory bodies of NLRP3 in alveolar macrophages are involved in this process, and the mechanism of NLRP3 inflammatory bodies is caused by hyperventilation in addition to mechanical injury. Decreased Keap1/Nrf2-ARE pathway inhibition and ROS clearance may also cause macrophage production of NLRP3 inflammatory bodies.

     

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