南方医科大学学报

南方医科大学学报 ›› 2022, Vol. 42 ›› Issue (9): 1374-1380.doi: 10.12122/j.issn.1673-4254.2022.09.14

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激活大麻素受体2可减轻实验性脓毒症大鼠的急性肺损伤

康惠文，蒋守芳，宋 倩，章义利   

  1. 华北理工大学公共卫生学院，河北 唐山 063210；浙江大学医学院附属金华医院健康管理中心，浙江 金华 325000
  • 发布日期:2022-09-28

Activation of cannabinoid receptor 2 alleviates acute lung injury in rats with lipopolysaccharide-induced sepsis

KANG Huiwen, JIANG Shoufang, SONG Qian, ZHANG Yili   

  1. School of Public Health, North China University of Science and Technology, Tangshan 063210, China; Health Management Center, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 325000, China
  • Published:2022-09-28

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摘要： 目的 探讨激活大麻素受体2（CB2）对大鼠脓毒症急性肺损伤的保护作用及机制。方法 将48只SD大鼠随机分为对照组、模型组、CB2激动剂组和P38 MAPK抑制剂组（12只/组）。对照组腹腔注射生理盐水，其余3组均腹腔注射脂多糖造模6 h；CB2激动剂组在注射脂多糖前30 min腹腔注射CB2激动剂JWH133（3 mg/kg），P38 MAPK抑制剂组在CB2激动剂组基础上提前30 min腹腔注射P38 MAPK抑制剂SB203580（5 mg/kg）。观察和检测肺组织病理学、含水率、液体清除率、炎症因子的变化情况，肺组织CB2、紧密连接的基因及蛋白表达情况以及P38 MAPK磷酸化情况。结果 与对照组相比，模型组大鼠的肺泡结构破坏严重，液体清除率、肺组织中CB2、occludin和ZO-1蛋白的mRNA及蛋白表达降低，肺组织含水率、P38 MAPK的磷酸化程度、肺灌洗液中TNF-α、IL-1β均增加，差异有统计学意义（P<0.05）。与模型组相比，CB2激动剂组肺泡形态有所恢复，但仍有炎性浸润，肺组织含水率、P38 MAPK磷酸化程度、肺灌洗液中TNF-α、IL-1β降低，液体清除率、肺组织CB2、occludin和ZO-1蛋白的mRNA及蛋白表达增加，差异均有统计学意义（P<0.05）。与CB2激动剂组相比，P38 MAPK抑制剂组肺泡结构有所恢复，肺组织P38 MAPK磷酸化程度、肺灌洗液中TNF-α、IL-1β水平降低，occludin、ZO-1蛋白表达增加，差异均有统计学意义（P<0.05），而CB2的mRNA及蛋白表达无变化（P>0.05）。结论 CB2激活后可通过抑制P38 MAPK信号通路，降低肺组织炎症因子释放，促进紧密连接蛋白表达，对实验性脓毒症大鼠急性肺损伤起到保护作用。

关键词: 大麻素受体2；P38 MAPK；紧密连接蛋白；脓毒症；大鼠

Abstract: Objective To investigate the protective effect of cannabinoid receptor 2 (CB2) activation against acute lung injury in rats with lipopolysaccharide (LPS)-induced sepsis and explore the underlying mechanism. Methods Forty-eight SD rats were randomly assigned into control group, model group, CB2 agonist group and P38 MAPK inhibitor group (n=12). In the latter 3 groups, the rats received intraperitoneal injection of LPS to induce sepsis, and the control rats were given saline injection. In CB2 agonist group, JWH133 (3 mg/kg) was injected intraperitoneally 30 min before LPS injection; in P38 MAPK inhibitor group, the rats received intraperitoneal injection of SB203580 (5 mg/kg) 30 min prior to JWH133 injection. The changes in lung histopathology, water content, fluid clearance rate, inflammatory factors, pulmonary expressions of CB2 and tight junction-related genes, and phosphorylation of P38 MAPK in the lung tissues were examined. Results The rat models of sepsis showed severe damage of alveolar structures with significantly decreased fluid clearance rate, lowered pulmonary expressions of CB2, occludin and ZO-1 mRNA and proteins, increased water content in the lung tissue, and increased phosphorylation level of P38 MAPK and TNF-α and IL-1β levels in lung lavage fluid (all P<0.05). Treatment with JWH133 improved alveolar pathology in the septic rats, but there was still inflammatory infiltration; lung tissue water content, phosphorylation of P38 MAPK, and TNF-α and IL-1β levels in lung lavage fluid were all significantly decreased, and the fluid clearance rate, pulmonary expressions of CB2, occludin and ZO-1 were significantly increased (all P<0.05). Additional treatment with SB203580 resulted in further improvements of alveolar pathologies, lowered phosphorylation levels of P38 MAPK in the lung tissue and TNF-α and IL-1β levels in lung lavage fluid, and increased the protein expressions of occludin and ZO-1 (P<0.05) without causing significant changes in mRNA and protein expression of CB2 (P>0.05). Conclusion In rats with LPS-induced sepsis, activation of CB2 can inhibit the p38 MAPK signaling pathway, reduce the release of inflammatory factors in the lung tissues, promote tight junction protein expressions, and thus offer protection against acute lung injury

Key words: cannabinoid receptor 2; P38 lightning MAPK; tight junction protein; sepsis; rats