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鼠尾草酚对脂多糖诱导的小鼠急性肺损伤的作用及机制分析

Roles and mechanism of carnosol for mice with lipopolysaccharide-induced acute lung injury

    摘要
  • 摘要:
      目的  探讨鼠尾草酚在脂多糖（LPS）诱导的小鼠急性肺损伤（ALI）中的作用及其分子机制。
      方法  将40只周龄10~12周的雄性C57BL/6J小鼠随机分为对照组、鼠尾草酚组、ALI组和治疗组（ALI+鼠尾草酚），每组10只。鼠尾草酚组和治疗组于LPS注射前1周给予鼠尾草酚20 mg/（kg·d）灌胃，持续7 d。ALI组和治疗组通过单次腹腔注射LPS（10 mg/kg）的方式构建小鼠ALI模型，对照组和鼠尾草酚组则注射等剂量生理盐水。注射LPS 12 h后，取小鼠主动脉血和肺组织，检测各组小鼠的动脉血氧分压pa（O2）、动脉血二氧化碳分压pa（CO2）、血清乳酸脱氢酶（LDH），记录肺湿干质量比值，HE染色观察各组小鼠肺组织损伤状况。采用免疫印迹法检测各组小鼠肺组织中铁死亡标志蛋白前列腺素内过氧化物合酶2（PTGS2）蛋白和谷胱甘肽过氧化物酶4（GPX4）蛋白的表达水平。检测小鼠肺组织中核转录因子红系2相关因子2（Nrf2）/血红素氧合酶-1（HO-1）信号通路相关蛋白的表达。
      结果  与对照组相比，ALI组小鼠肺组织出现明显肺水肿、炎症细胞和红细胞浸润等损伤特征，肺湿干质量比值、气道压、pa（CO2）升高，pa（O2）降低，肺组织中PTSG2蛋白表达升高、GPX4蛋白降低，Nrf2、HO-1蛋白表达降低，差异均有统计学意义（P < 0.05）；与ALI组相比，治疗组小鼠肺组织损伤减轻，肺湿干质量比值降低，pa（O2）升高，pa（CO2）降低，肺组织中PTSG2蛋白表达降低、GPX4蛋白升高，Nrf2、HO-1蛋白表达升高，差异均有统计学意义（P < 0.05）。
      结论  鼠尾草酚具有减轻小鼠ALI的作用，其可能通过调控Nrf2/HO-1抑制铁死亡而发挥肺保护作用。

     

    Abstract:
      Objective  To explore the role of carnosol for mice with lipopolysaccharide (LPS)-induced murine acute lung injury (ALI) and its molecular mechanism.
      Methods  A total of 40 male C57BL/6 mice aged 10 to 12 weeks were randomly divided into control group (n=10), carnosol group (n=10), ALI group(n=10) and treatment group (ALI+ carnosol, n=10). The carnosol group and the treatment group were given intragastric administration of carnosol for 20 mg/(kg·d) 1 week before LPS injection. The ALI group and the treatment group were injected with a single intraperitoneal injection of LPS (10 mg/kg) to construct a murine ALI model, while the control group and the carnosol group were injected with the same dose of normal saline. After 12 hours of LPS injection, the mouse aortic blood and lung tissues were collected, and the partial pressure of oxygenpa(O2), carbon dioxidepa(CO2)in the arterial blood, and serum lactic dehydrogenase (LDH) were measured. Lung wet-to-dry weight ratio was recorded, and the tissue damage was detected by HE staining. Western blot was used to detect the protein expression levels of ferroptosis markers including prostaglandin intraperoxidase synthase 2 (PTGS2) protein and glutathione peroxidase 4 (GPX4) protein in lung tissues of mice in each group. Finally, the expression of nuclear transcription factor red 2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway related proteins in lung tissues of mice was detected.
      Results  Compared with the control group, the ALI group showed obvious damage such as pulmonary edema, inflammatory cells and red blood cells infiltration, the wet-to-dry weight ratio, the airway pressure and pa(CO2) were significantly decreased, pa(O2)was significantly increased, the expression of PTSG2 protein in lung tissue was increased, GPX4 proteinwas decreased, and the expression levels of NRF2 and HO-1 protein were significantly reduced (P < 0.05). Compared with the ALI group, the lung injury in the treatment group was significantly reduced, the wet-to-dry weight ratio was significantly reduced, pa(O2)was significantly increased, pa(CO2) was significantly decreased, the expression of PTSG2 protein in lung tissue was decreased, GPX4 protein was increased, the expression levels of NRF2 and HO-1 protein were significantly increased (P < 0.05).
      Conclusion  Carnosol has the potential to protect against ALI in mice, and plays the role in inhibiting ferroptosis by activating NRF2/HO-1 pathway.

     

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