| 李艳艳,潘频华,苏晓丽,胡成平,刘 帅,李海涛,黎皓思,李 毅,戴敏慧,毛 志,李 千.TLR4-Nrf2/HO-1信号通路在小鼠机械通气所致肺损伤的作用研究[J].,2018,(20):3812-3816 |
| TLR4-Nrf2/HO-1信号通路在小鼠机械通气所致肺损伤的作用研究 |
| TLR4 - Nrf2/HO-1 Signaling Pathway in Ventilator-induced Lung Injury in Mice |
| 投稿时间：2018-04-01 修订日期：2018-04-28 |
| DOI：10.13241/j.cnki.pmb.2018.20.003 |
| 中文关键词: Toll样受体4 核因子-E2相关受体2 血红素氧化酶-1 机械通气相关肺损伤 |
| 英文关键词: Toll -like receptor-4 NF-E2（Nuclear factor-erythroid 2）related factor2 Heme oxygenase 1 VILI |
| 基金项目:国家自然科学基金项目（81470266） |
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| 中文摘要: |
| 摘要 目的：机械通气作为一重要措施，拯救呼吸衰竭患者的生命，有致肺血管炎症及渗透增加等病变的可能，即VILI。本研究旨在明确VILI是否受潮气量、Toll样受体4（Toll-like receptor-4,TLR4）基因敲除及核因子-E2相关受体2/血红素氧化酶-1(Nuclear factor-erythroid 2 related factor2/heme oxygenase 1，Nrf2/HO-1）表达的激活关联是否存在。方法：TLR4基因缺失和野生型（WT）小鼠分别分为对照（CON），低潮气量（low tidal volume，LTV）和高潮气量（high tidal volume，HTV）组。给小鼠禁食、禁水12小时后，麻醉小鼠，做气管切开，将气管导管经口插入，通气4小时，呼气末正压（PEEP）2 cm H2O，R：100次/分钟，吸呼比1：2；CON组仅气管插管。小鼠处死，测湿/干重比（W/D）。肺组织依次：HE染色组织学评价；评价肺损伤评分；测定肺炎症因子表达：肿瘤坏死因子-α( tumor necrosis factor-α，TNF-α) 及白介素-1β( interleukin-1β，IL-1β)；免疫组化及免疫印迹法，测Nrf2蛋白值；测HO-1蛋白值。结果：在WT+HTV组，Nrf2和HO-1的表达比较WT+LTV组明显升高，但受到TLR4基因敲除的调节，相应的TLR4基因敲除组升高更明显。肺损伤评分、湿/干比在WT+HTV组增加，相应的TLR4基因敲除组升高更显著。结论：HTV通气可致小鼠VILI。VILI小鼠肺中的Nrf2/HO-1表达升高，TLR4基因缺失可以升高Nrf2/HO-1表达，保护肺组织，减轻VILI。 |
| 英文摘要: |
| ABSTRACT Objective: Mechanical ventilation is a life-saving procedure for patients with acute respiratory failure, although it may cause pulmonary vascular inflammation and leakage, leading to ventilator-induced lung injury (VILI). The purpose of this study was to determine the association between Nrf2/HO-1 expression in lung tissue in mice and the levels of VILI with different tidal volume. Futhermore, we examined the activation of Nrf2/HO-1 expression is linked to the presence of toll-like receptor 4 (TLR4). Methods: Both TLR4 KO and matched wild type (WT) mice were assigned to control, low tidal volume (LTV) and high tidal volume (HTV) groups. After given 12 hours of fasting and water-deprivation, mice were anesthetized, orotracheally intubated and ventilated for 4 hours with positive end-expiratory pressure of 2 cm H2O, respiratory rate of 40 breaths per minute and inspiration /expiration ratio of 1:2. Control groups were only given intratracheal catheter but not given mechanical ventilation. After weaning, mice were sacrificed, the wet/dry (W/D) weight ratio and the lung injury score were evaluated, histological assessment were performed by hematoxylin-eosin (H&E) staining, the expression of TNF-αand IL-1β in lung tissue were examined and the expression of Nrf2 and HO-1 in lung tissue were examined by Immunohistochemistry and western blot. Results: The expression of Nrf-2, HO-1 in the lung tissue were elevated in mice of WT+HTV groups compared with the control groups and WT+LTV groups, which was largely attenuated by abrogation of TLR4. Also, an increase of lung injury score and W/D weight level seen in mice of WT+HTV groups were also alleviated in TLR4 KO mice. Conclusion:High tidal volume ventilation can induce ventilator-induced lung injury in mice. TLR4 mediates Nrf2/HO-1 signaling pathway during different tidal volume in ventilator-induced lung injury in mice, which may play an protectable role in the pathogenesis of VILI. |
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