| In recent years,due to national development needs and related strategic strategies,more and more people have been stationed and resettled in the plateau areas.Compared with plain areas,there are many different special natural conditions,such as hypobaric hypoxia,high cold,dryness,strong ultraviolet light,etc.Among them,hypobaric hypoxia is the most serious threat to human health.High-altitude pulmonary hypertension（HAPH）is one of the more serious diseases as a consequence of hypoxia.Pulmonary hypertension（PH）is a chronic progressive disease characterized by persistent and significantly increased pulmonary artery pressure,which can lead to right heart hypertrophy and right heart dysfunction,and may eventually lead to structural changes of left heart and whole heart.There are five categories of pulmonary hypertension,of which HAPH is listed in category 3.Before entering the plateau,HAPH patients did not have other conditions that could cause pulmonary hypertension,which was only caused by reduced oxygen pressure.HAPH is characterized by the structural and functional remodeling of pulmonary arteries,especially the distal pulmonary small arteries,in which smooth muscle cells play an important role.HAPH is characterized by structural and functional remodeling of pulmonary arteries,especially distal pulmonary arterioles,in which smooth muscle cells play an important role.Hypobaric hypoxia can lead to increased proliferation of pulmonary artery smooth muscle cells,inhibition of apoptosis,and conversion from contractile phenotype to synthetic phenotype.Such changes in biological characteristics are the basis of pulmonary artery remodeling after hypobaric hypoxia.At present,in addition to reducing the height of the treatment for HAPH,drugs such as highly selective blockers and nitric oxide related drugs are often used in clinical treatment,but the curative effect is very limited,and it is difficult to completely reverse the remodeling of pulmonary vascular structure and function.Oxygen supply in plateau areas may be the most effective means to prevent HAPH.According to the principle of aviation oxygen supply,at an altitude of 5000 m（405.2mm Hg）,when the oxygen concentration in the inhaled air is about 42%,the physiological equivalent height of oxygen supply is sea level（760 mm Hg）,at which time the body will not suffer from hypoxia.However,in plateau areas,it is unrealistic to supply oxygen for 24hours a day.In our previous work,we found that intermittent short-term artificial gravity for 1 hour a day can effectively prevent region-specific remodeling of partial arterial function and structure caused by simulated weightlessness.Inspired by this,we found that daily intermittent short-duration reoxygenation can effectively slow down the occurrence and development of high altitude pulmonary hypertension.Among the observed schemes,the protection effect of three times of oxygen supply per day is better when the duration of oxygen supply is 1 hour and the physiological equivalent height of oxygen supply is sea level.When we increase the frequency and total duration of oxygen supply,the protective effect decreases instead,which may be related to the increased oxidative stress damage.Different oxygen supply time and physiological equivalent height may affect the oxygenation status of the body and thus the protective effect.There should be an optimal combination between the physiological equivalent height of oxygen supply and the length of oxygen supply.Therefore,in order to improve the effect of intermittent short-duration reoxygenation,it may be an effective way to change the time and height of oxygen supply or reduce the level of oxidative stress in the body.There are many factors affecting the occurrence and development of pulmonary hypertension,among which uric acid（UA）plays a certain role in the occurrence and development of pulmonary hypertension.UA and PH interact with each other.High concentration of UA promotes pulmonary vascular remodeling,and severe PH will also cause an increase of UA level in the body.UA is the final product of human purine metabolism.It can be produced in different organs and tissues,such as liver,muscle,kidney,blood vessel,etc.The liver is the main organ that produces UA,and the kidney is the main organ that excretes UA.The last two reactions in the biochemical chain of UA production,namely,the transformation from hypoxanthine to xanthine and the transformation from xanthine to UA,are catalyzed by xanthine oxidase（XOD）,and a large number of superoxide anion（O2-）is produced at the same time,which destroys the balance of oxidative stress in the body.The increase of serum uric acid（SUA）has a great impact on the health of the body.In addition to causing gout,it is also related to systemic diseases such as kidney,respiratory,endocrine and cardiovascular diseases.The causes of various diseases caused by UA may not be limited to the role of UA itself.The change in UA level may also be one of the reasons for the aggravation of oxidative stress damage in the body.The prevalence of hyperuricemia is high in plateau areas,but whether hypobaric hypoxia is an independent factor inducing UA elevation has not been reported.Therefore,before exploring the relationship between UA and intermittent short time oxygen supply to protect hypoxic pulmonary hypertension,it is necessary to clarify the effect of hypoxic hypoxia and intermittent short time oxygen supply on the level of UA in the body.In order to obtain better protective effects and benefits,male Sprague Dawley（SD）rats were used as the research object in this work.The animal altitude chambers were used to simulate the 5000 m high hypobaric hypoxia environment.The hypobaric hypoxia rats and intermittent short time oxygen supply rats lived in this environment for 2 weeks.The intermittent oxygen supply scheme was to supply oxygen three times a day,the effects of different duration of single oxygen supply or different physiological equivalent height of oxygen supply on the protective effect were compared.The protective effect was determined by measuring the right ventricular pressure and right ventricular hypertrophy index of rats.By measuring the content of serum UA,the activity of liver XOD,and the expression of urate anion transporter 1（URAT1）in the kidney,we explored the effect of hypobaric hypoxia and intermittent short-duration reoxygenation on the level of SUA in the body and the possible reasons.The effect of SUA on HAPH and the effect of intermittent short time oxygen supply on the protection of HAPH under hypobaric and hypoxia environment and its possible mechanism were discussed through the study of the inhibition of XOD activity by Febuxostat from animal and cell levels.The main results of this work are as follows:1.The duration and physiological equivalent height of intermittent short-duration reoxygenation affect its protective effect on pulmonary hypertension in rats with hypobaric hypoxia.（1）The weight of rats in hypobaric hypoxia group and intermittent short-duration reoxygenation group was significantly lower than that of control rats,but the weight of rats in the 1.5-hour single oxygen supply group was significantly higher than that in other oxygen supply groups;（2）The hematocrit（HCT）of rats in hypobaric hypoxia group and intermittent short-duration reoxygenation group increased which compared with in the control group,but each oxygen supply group was lower than that in hypobaric hypoxia group;（3）The RV/LV+S and RVSP were obviously higher than those in the control group,but the increase amplitude of 1 hour and 0.5 hour of single oxygen supply was significantly lower than that of the hypobaric hypoxia group,and there was no significant difference between the two groups,while there was no significant difference between the rats in the1.5 hour of single oxygen supply and the 3000m high oxygen supply group and the hypobaric hypoxia group;（4）There was no significant difference in the ratio of heart weight to body weight and left heart weight to body weight in each group;（5）Compared with the control group,the content of malondialdehyde in serum and lung tissue of rats in each group was significantly higher,and the rats in each oxygen supply group were significantly higher than those in the hypobaric hypoxia group,while the increase in the 1.5-hour single oxygen supply group was significantly higher than that in other oxygen supply groups.2.Intermittent short-duration reoxygenation can reduce the increase of blood uric acid level in rats caused by hypobaric hypoxia.（1）5000m 2-week hypobaric hypoxia exposure can significantly increase the level of SUA in rats,and intermittent short-duration reoxygenation can significantly reduce the increase of SUA;（2）The activity of XOD in the liver of rats in hypobaric hypoxia group was significantly increased,and there was no significant difference between the activity of XOD in the intermittent short-duration reoxygenation group and the hypobaric hypoxia group;（3）The expression of URAT1 in the kidney of rats in hypobaric hypoxia group was significantly increased,and intermittent short-duration reoxygenation could significantly reduce the increase of URAT1.It is suggested that intermittent short-duration reoxygenation can directly reduce the level of uric acid in blood,and its action may be through reducing the reabsorption of uric acid in kidney.3.Further reduce the production of uric acid by febuxostat to improve the protective effect of intermittent short-duration reoxygenation on pulmonary hypertension in rats with hypobaric hypoxia（1）Gastric feeding of febuxostat can reduce the blood uric acid level of rats in hypobaric hypoxia group,and further reduce the blood uric acid level of rats in intermittent short-duration reoxygenation group;（2）Gastric feeding of febuxostat can further improve the protective effect of intermittent short-duration reoxygenation on HAPH,but it has no obvious effect on the HAPH of rats in hypobaric hypoxia group:on the basis of intermittent short-duration reoxygenation,gastric feeding of febuxostat can（1）further reduce the right ventricular systolic pressure and right ventricular hypertrophy index;（2）Further significantly reduce the intrapulmonary arterioles（diameter 50-200μm）caused by hypobaric hypoxia.The increase of middle film thickness;（3）Further significantly reduce the intrapulmonary myogenic small vessels（diameter 25-75μm）caused by hypobaric hypoxia increase in proportion;（3）Compared with the intermittent short-time oxygen supply group,the use of febuxostat can significantly improve the proliferation of rat pulmonary artery smooth muscle cells and the conversion from contractile phenotype to synthetic phenotype caused by hypoxia.（4）In hypobaric and hypoxic environment,feeding rats with febuxostat by stomach:（1）can significantly reduce the content of MDA in serum and lung tissue;（2）It has no obvious effect on CAT activity of lung tissue;（3）It can significantly increase GSH-PX activity in lung tissue;（4）It can significantly increase the activity of SOD in lung tissue.Under the condition of intermittent short time oxygen supply,the simultaneous gastric administration of febuxostat can（1）significantly reduce the content of MDA in serum and lung tissue;（2）It can significantly increase CAT activity of lung tissue;（3）There was no significant effect on GSH-PX activity in lung tissue;（4）It can significantly increase the activity of SOD in lung tissue.Conclusions:1.Intermittent short-duration reoxygenation for both 1 h and 0.5 h has a significant protective effect on rats with hypobaric hypoxic pulmonary hypertension.The protective effect decreased when the single oxygen supply lasted for 1.5 hours,and changed the protective effect may be related to the change of oxidative stress level.When the physiological equivalent height of oxygen supply is 3000 m,intermittent short-duration reoxygenation has no obvious protective effect.The effect of oxygen supply duration and physiological equivalent height of oxygen supply may be different in different physiological systems.2.Hypobaric hypoxia can significantly increase the level of blood uric acid in rats,and intermittent short-duration reoxygenation at ground level three times a day and one hour each time can significantly reduce the extent of blood uric acid increase caused by hypobaric hypoxia,and its mechanism may be related to the reduction of renal reabsorption of uric acid.3.Febuxostat can reduce the level of blood uric acid in rats with hypobaric hypoxia,but has no significant effect on HAPH caused by hypobaric hypoxia;Intermittent short-time oxygen supply combined with the use of febuxostat can further reduce the level of blood uric acid in rats,and can further improve the protective effect of intermittent short-time oxygen supply on hypobaric hypoxic pulmonary hypertension;Compared with the intermittent short-time oxygen supply group,the use of febuxostat can significantly improve the proliferation of rat pulmonary artery smooth muscle cells and the conversion from contractile phenotype to synthetic phenotype caused by hypoxia. |
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