Objective To investigate the effects and molecular mechanism of Notoginsenoside R1 on hypobaric hypoxia-induced high-altitude pulmonary edema based on nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)/glutathione peroxidase 4(GPX4)signaling pathway.Methods Forty-two 6-week-old male SD rats were acclimatized and fed for one week,and then randomized into the Control group,negative control group(NGR1,100 mg·kg-1),model group(HH),Notoginsenoside R1 low dose group(NGR1-low,50 mg·kg-1),Notoginsenoside R1 high dose group(NGR1-high,100 mg·kg-1),and dexamethasone group(Dex,4 mg·kg-1),with seven rats in each group.After the drug administration group was administered with Notoginsenoside R1 or dexamethasone by intraperitoneal injection,the hypobaric hypoxia simulation chamber was used to simulate the plateau environment for modeling.Detect the total protein concentration in bronchoalveolar lavage fluid(BALF)and measure the lung wet/dry weight ratio(W/D);ELISA to measure inflammation levels of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),and IL-1β in BALF;hematoxylin-eosin(HE)staining to visualize pathomorphologic changes in the lungs of each group;biochemical kit detect the content and activity of reactive oxygen species(ROS),superoxide dismutase(SOD),and reduced glutathione(GSH)in the lung tissues;Western blot to detect the protein expression of Nrf2,HO-1,GPX4,SLC7A11 and NOX1 in lung tissues.Results Compared with the Control group,the total protein concentration in the BALF of rats in the HH group was markedly increased(P<0.01),and the lung W/D was markedly increased(P<0.01);lung histopathology showed obvious thickening of the alveolar wall,interstitial edema,hemorrhage and massive inflammatory exudation in the alveolar lumen,alveolar septa,and interstitium of the lungs;the levels of TNF-α(P<0.001),IL-6(P<0.01),and IL-1β(P<0.0001)in the BALF were significantly elevated;ROS content was significantly increased(P<0.01),and SOD(P<0.01)and GSH(P<0.01)activities were significantly decreased in lung tissues;the expression of Nrf2 in the nucleus of lung was markedly decreased(P<0.001),and that in the cytoplasm of lung was markedly increased(P<0.05),and the expression of HO-1(P<0.01),GPX4(P<0.01),and SLC7A11(P<0.05)was significantly decreased,and that of NOX1 was significantly increased(P<0.01).Compared with the HH group,the total protein concentration in the BALF of rats in each drug intervention group was significantly reduced,and the lung W/D was significantly reduced;the lung histopathology was significantly improved;the levels of TNF-α,IL-6,and IL-1β in the BALF were significantly decreased;the content of ROS in the lung tissues was significantly reduced,and the activities of SOD and GSH were significantly elevated;the expression of Nrf2 in the nucleus of lung was markedly increased,the expression of Nrf2 in the cytoplasm of lung was markedly decreased,the expression of HO-1,GPX4,SLC7A11 was markedly increased,and the expression of NOX1 was markedly decreased.Conclusion Notoginsenoside R1 inhibits hypobaric hypoxia-induced ferroptosis and attenuates pulmonary edema,lung inflammation and oxidative stress by a mechanism that may be related to the regulation of the Nrf2/HO-1/GPX4 pathway.

Objective To investigate the effects and molecular mechanism of Notoginsenoside R1 on hypobaric hypoxia-induced high-altitude pulmonary edema based on nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)/glutathione peroxidase 4(GPX4)signaling pathway.Methods Forty-two 6-week-old male SD rats were acclimatized and fed for one week,and then randomized into the Control group,negative control group(NGR1,100 mg·kg-1),model group(HH),Notoginsenoside R1 low dose group(NGR1-low,50 mg·kg-1),Notoginsenoside R1 high dose group(NGR1-high,100 mg·kg-1),and dexamethasone group(Dex,4 mg·kg-1),with seven rats in each group.After the drug administration group was administered with Notoginsenoside R1 or dexamethasone by intraperitoneal injection,the hypobaric hypoxia simulation chamber was used to simulate the plateau environment for modeling.Detect the total protein concentration in bronchoalveolar lavage fluid(BALF)and measure the lung wet/dry weight ratio(W/D);ELISA to measure inflammation levels of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),and IL-1β in BALF;hematoxylin-eosin(HE)staining to visualize pathomorphologic changes in the lungs of each group;biochemical kit detect the content and activity of reactive oxygen species(ROS),superoxide dismutase(SOD),and reduced glutathione(GSH)in the lung tissues;Western blot to detect the protein expression of Nrf2,HO-1,GPX4,SLC7A11 and NOX1 in lung tissues.Results Compared with the Control group,the total protein concentration in the BALF of rats in the HH group was markedly increased(P<0.01),and the lung W/D was markedly increased(P<0.01);lung histopathology showed obvious thickening of the alveolar wall,interstitial edema,hemorrhage and massive inflammatory exudation in the alveolar lumen,alveolar septa,and interstitium of the lungs;the levels of TNF-α(P<0.001),IL-6(P<0.01),and IL-1β(P<0.0001)in the BALF were significantly elevated;ROS content was significantly increased(P<0.01),and SOD(P<0.01)and GSH(P<0.01)activities were significantly decreased in lung tissues;the expression of Nrf2 in the nucleus of lung was markedly decreased(P<0.001),and that in the cytoplasm of lung was markedly increased(P<0.05),and the expression of HO-1(P<0.01),GPX4(P<0.01),and SLC7A11(P<0.05)was significantly decreased,and that of NOX1 was significantly increased(P<0.01).Compared with the HH group,the total protein concentration in the BALF of rats in each drug intervention group was significantly reduced,and the lung W/D was significantly reduced;the lung histopathology was significantly improved;the levels of TNF-α,IL-6,and IL-1β in the BALF were significantly decreased;the content of ROS in the lung tissues was significantly reduced,and the activities of SOD and GSH were significantly elevated;the expression of Nrf2 in the nucleus of lung was markedly increased,the expression of Nrf2 in the cytoplasm of lung was markedly decreased,the expression of HO-1,GPX4,SLC7A11 was markedly increased,and the expression of NOX1 was markedly decreased.Conclusion Notoginsenoside R1 inhibits hypobaric hypoxia-induced ferroptosis and attenuates pulmonary edema,lung inflammation and oxidative stress by a mechanism that may be related to the regulation of the Nrf2/HO-1/GPX4 pathway.