P38MAPK-Nrf2-HO-1信号通路在大鼠机械通气所致肺损伤中作用的研究  

The role of P38MAPK-Nrf2-HO-1 signaling pathway in the lung injury induced by mechanical ventilation in rats

作　　者：周吉 陈硕[1] 邹圣强[1] ZHOU Ji;CHEN Shuo;ZOU Shengqiang(Emergency Department of Yixing People’s Hospital Affiliated to Jiangsu University,Yixing 214200,China)

机构地区：[1]江苏大学附属宜兴人民医院急诊科,宜兴214200

出　　处：《中华灾害救援医学》2020年第10期554-558,共5页Chinese Journal of Disaster Medicine

基　　金：江苏大学医学临床科技发展基金项目(JLY20180061)。

摘　　要：目的研究P38MAPK-Nrf2-HO-1信号通路在机械通气肺损伤中各因子的表达情况,明确该通路在抗氧化应激中的相关作用及机制。方法50只大鼠分成5组,A组正常对照组、B组为大潮气量通气组(High Tidal Volume,HTV)、C组大潮气量通气+P38MAPK抑制剂组、D组大潮气量通气+P38MAPK抑制剂+Nrf2抑制剂组、E组大潮气量通气+P38MAPK抑制剂+锌原卟啉组。A组正常对照;B组行大潮气量机械通气2 h;C、D、E三组在实验前2 h应用特异性抑制剂预处理再行大潮气量机械通气2 h。实验结束后取肺组织光镜观察肺组织病理学改变并进行弥漫性肺泡损伤系统(diffuse alveolar damage,DAD)评分;测定髓过氧化物酶(myeloperoxidase,MPO)活性;计算肺湿/干质量比(W/D);酶联免疫吸附试验(ELISA)检测肺泡灌洗液中肿瘤坏死因子(TNF-α)的水平;Western Blot检测P38MAPK和H0-1表达情况。结果P38MAPK抑制剂组和大潮气量通气组、P38MAPK抑制剂组+Nrf2抑制剂组、大潮气量通气+P38MAPK抑制剂+锌原卟啉组分别比较DAD评分、W/D、MPO及TNF-α差异均具有统计学意义(P<0.05);大潮气量通气组、P38MAPK抑制剂组+Nrf2抑制剂组、大潮气量通气+P38MAPK抑制剂+锌原卟啉组之间相互比较DAD评分、W/D、MPO及TNF-α差异均无统计学意义(P>0.05);HO-1的表达量在P38MAPK抑制剂组中最高,与其他各组比较差异均有统计学意义(P<0.05)。结论使用P38MAPK抑制剂可以显著减少大鼠机械通气相关肺损伤,其机制是通过上调体内Nrf2表达,进而启动内源性抗氧化途径,然后激活下游HO-1的表达来降低肺毛细血管通透性,抑制炎症因子、炎症细胞的趋化,抑制细胞凋亡。Objective To study the expression of various factors of P38MAPK-Nrf2-HO-1 signaling pathway in mechanically ventilated lung injury,and to clarify its effects and mechanisms in anti-oxidation stress.Methods Fifty rats were divided into 5 groups,group A(normal control group),group B[high tidal volume ventilation group(High Tidal Volume,HTV)],group C(high tidal volume ventilation+P38MAPK inhibitor group),group D(high tidal volume ventilation+P38MAPK inhibitor+Nrf2 inhibitor group),group E(high tidal volume ventilation+P38MAPK inhibitor+zinc protoporphyrin group).Group A was a normal control group;Group B received high tidal volume mechanical ventilation for 2 hours;Groups C,D,and E were pretreated with specific inhibitors 2 hours before the experiment,followed by mechanical ventilation with high tidal volume for 2 h.After the experiment,the lung tissue was taken to observe the pathological changes of lung tissue under light microscope and to evaluate diffuse alveolar damage(DAD)score;The myeloperoxidase(MPO)activity was measured;lung wet/dry mass ratio(W/D)was calculated;enzyme-linked immunosorbent assay(ELISA)was used to detect the level of tumor necrosis factor(TNF-α)in the alveolar lavage fluid;Western Blot was applied to detect the expression of P38MAPK and H0-1.Results The differences of W/D,MPO and TNF-αin group C,D and E were statistically significant(P<0.05);There was no significant difference in DAD score,W/D,MPO and TNF-αbetween group B,D and E(P>0.05);The expression level of HO-1 was the highest in the P38MAPK inhibitor group,and the differences were statistically significant compared with other groups(P<0.05).Conclusions The use of P38MAPK inhibitors can significantly reduce the mechanical ventilation-related lung injury in rats.Its mechanism is acted through up-regulating the expression of Nrf2 in the body,which in turn activates the endogenous antioxidant pathway,and then activates the downstream HO-1 expression to reduce lung capillary permeability,inhibit the chemotaxis of inflammatory factors and

关 键 词：机械通气 肺损伤 P38MAPK HO-1 NRF2 

分 类 号：R563.8[医药卫生—呼吸系统]