| Objective: 1.To establish a rat model of high altitude pulmonary edema with high reproducibility through low pressure hypoxia animal test chamber,and to explore the effect of exercise combined with acute hypobaric hypoxia and cold on pulmonary edema in rats.2.To study the intervention effect of 7-hydroxyethyl chrysin on high altitude pulmonary edema rats and its preliminary mechanism.Methods: 1.120 Wistar rats were randomly divided into Normal control group,Model-I(6000 m),Model-II(6000 m + 2?),Model-III(6000 m + 2? + running exercise),Model-IV(6000 m + day and night temperature difference 12?/2?),and Model-V group(6000 m + day and night temperature difference 12?/2? + running exercise).The rats in each group were treated with preconditions.The high altitude pulmonary edema model was screened according to the preliminary indicators as pathological changes of lung tissue,lung water content and pulmonary microvascular permeability.The model was further evaluated by the oxidative stress and inflammatory related factors in lung tissue,and the stability of the model was investigated by reproducibility experiment.2.100 Wistar rats were randomly divided into normal control group(sterile water),high altitude pulmonary edema model group(sterile water),acetazolamide group(200 mg/kg),chrysin group(350 mg/kg),and 7-hydroxyethyl chrysin group(350 mg/kg).Reproduce the rat model of high altitude pulmonary edema.The drugs in each group were administered by intragastric administration for 6 days.The effect of chrysin and 7-hydroxyethyl chrysin on high altitude pulmonary edema in rats were evaluate by observing the pathological changes of lung tissue, detecting the lung water content and pulmonary microvascular permeability,analyzing the blood gas and blood routine,detecting the oxidative stress,energy metabolism,inflammatory factor,pulmonary vascular permeability related indicators,pulmonary artery pressure related indicators and alveolar clearance related indicators.The preliminary mechanism of 7-hydroxyethyl chrysin in preventing high altitude pulmonary edema in rats was explored through the detection the related genes expression by Real-Time PCR.Results: 1.Model-IV and model-V groups showed obvious pathological changes in lung tissue,lung water content and pulmonary microvascular permeability were increased,which changes in the model-V were more significant.Thus,the model-V was initially screened for rat model of high altitude pulmonary edema.At the same time,the expression of oxidative stress and inflammatory factors were detected.The results showed that the rats in model-V had obvious oxidative stress and inflammatory reaction.The levels of MPO,MDA,and H2O2 in lung tissue were significantly increased,the levels of SOD,CAT,GST,GPX and GSH were decreased,the levels of serum NF?B p65,TNF-?,IL-1?,IL-6,and the expression of VCAM-1 and s ICAM-1 in the lung tissue were increased.Further detection of lung water content and pulmonary microvascular permeability in model-IV and model-V through reproducibility test showed that the water content of lung tissue and pulmonary microvascular permeability were significantly increased under the condition of model-V,and showed obvious pulmonary edema,indicating that model-V is the more stable and reliable rat model of high altitude pulmonary edema.2.7-hydroxyethyl chrysin can significantly improve the pathological changes of lung tissue in rats,reduced lung water content and pulmonary microvascular permeability,relieved the rapid decline in body weight in rats,made blood gas and blood indicators close to the normal level;Reduced MPO,MDA,H2O2 level,enhanced SOD,GST,GPX activity,increased GSH content,no significant effect on CAT,increased scavenging ability of ·OH and O2-· in lung tissue,and can significantly weaken the high altitude pulmonary edema oxidative stress response;Increased ATP production,and had no effect on LD/Pyr,suggesting that 7-hydroxyethyl chrysin may increase the use of oxygen in rats,but there is no significant effect on the glycolytic pathway;Down-regulate the expression of NF?B p65 protein,reduced the production of inflammatory factors by its regulation;Significantly increased NO,CO content,increased e NOS/ET-1 ratio,inhibition of excessive pulmonary vascular contraction,and reduced pulmonary artery pressure;Down-regulated the expression of HIF-1? and VEGFA gene,up-regulated the expression of Occludin gene and protein,and reduced the pulmonary microvascular permeability;Up-regulated the AQP1,?-ENa C and Na+K+-ATPase gene and protein expression,increased the alveolar fluid clearance ability to improve alveolar active reabsorption dysfunction.Conclusion: 1.Establish a rat model of high altitude pulmonary edema with good reproducibility,and the conditions were determined.2.7-hydroxyethyl chrysin has a good effect on the prevention of high altitude pulmonary edema in rats.And its effect is better than acetazolamide and chrysin.The main preventive effect may be reflected in improving the physiological and pathological changes in rats,inhibit the oxidative stress and inflammatory response,reduce pulmonary artery pressure and pulmonary vascular permeability,and improve alveolar fluid scavenging ability.3.The activation of downstream genes after HIF-1 activation was an important pathway for the prevention of high altitude pulmonary edema by 7-hydroxyethyl chrysin,and the up-regulation of ?-ENa C and Na+K+-ATPase gene in improving alveolar fluid reabsorption dysfunction is of great significance. |
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