The Protective Effects Of Ethyl Pyruvate On High-altitude Pulmonary Edema

ObjectiveHigh-altitude pulmonary edema?HAPE?is a series of critical pathophysiol ogical change usually occurred in the first time of coming to high altitude are a due to the low pressure and hypoxia environment.Recent studies on highaltitude pulmonary edema have shown that oxidative stress and inflammatory play an important role in the pathogenesis of HAPE,but the specific pathoge nesis of HAPE has not yet been fully elucidated.At present,treatment about HAPE includes oxygen therapy,NO treatment and a variety of drug treatme nt such as aminophylline,dexamethasone,etc..According to the general con ditions of patient and site conditions,different drugs or drugs combined with oxygen therapy have played a certain relief effect.Ethyl pruvate?EP?is an e ster of pyruvate,which not only remedies tissue damage mediated by redox reactions and clears endogenous H₂O₂,but also reduces the secretion of proi nflammatory cytokines and gets rid of hydroxyl,peroxynitrite and other reactiv e oxygen species?ROS?.Therefore,we speculate that ethyl pyruvate can inh ibit the development of HAPE by anti-inflammatory and anti-oxidative effects.Methods 1.Establishment of rat high altitude pulmonary edema model24 rats were randomly divided into plain normal group?N?,simulated acute high altitude hypoxia?H?1d,2d,3d group?n=6?,H group rats were placed in hypoxia chamber simulated high altitude 6000 m plateau and exposure for 1d,2d,3d,24h/d,continuous decompression.The normal group?N group?rats were kept in the plain environment.Then rat lung tissue wet/dry ratio?W/D?,glutathione?GSH?,malondialdehyde?MDA?and superoxide dismutase?SOD?of lung tissue were measured in each group.HE histopathological changes were observed.2.To explore the protective effect of ethyl pyruvate on high-altitude pulmonaryedemaThirty SD rats were randomly divided into control group?control group?,high altitude hypoxia model group?H3d group?,ethyl pyruvate group?EP 1mg/kg,EP 5mg/kg,EP 10mg/kg group??n=6?.Control group rats were intraperitoneally injected with lactic acid ringer sodium injection each 1ml,continuous injection for 2 days,plain environment normal feeding;H3d group rats were intraperitoneally injected with lactic acid ringer sodium injection each 1ml,continuous injection for 2 days,and then were placed in hypoxia chamber simulated high altitude 6000 m plateau and exposure for 3days,24h/d,continuous decompression;rats of EP group were separately injected intraperitoneally with ethyl pyruvate 1mg/kg,5mg/kg and 10mg/kg for 2days.Animals were free to drink and eat.After the completion of the injection,animals were placed in the hypoxia chamber simulated 6000 m altitude continuous exposure 3d,24h/d.The levels of IL-6,IL-10,IL-1? and TNF-? in serum were detected by ELISA kit.The expression of p65,IL-6,COX-2 and STAT3 were detected by Western blotting.The histopathological changes of lung tissue were observed by HE pathological sections of lung tissue.Results 1.Establishment of rat high altitude pulmonary edema model?1?Changes of oxidative stress in hypoxic environmentCompared with the normal group?N group?,the W/D and the content of MDA in lung tissue homogenate of rats gradually increased at 1d,2d and 3d after exposed in hypoxic environment?P<0.01?.Among them,H3 d group increased significantly?P<0.01?.The activity of SOD and level of GSH in the lung tissue homogenate were obviously decreased at 1d,2d and 3d after exposed in hypoxic environment?P<0.01?.The changes in H3 d group were most significant?P<0.01?.?2?Morphological observationWith the prolongation of exposure time in hypoxic environment,the pathological changes of lung tissue in H1 d,H2d and H3 d groups were observed gradually severe.Telangiectasia was observed in lung tissue.Pink exudate was visible in alveolar cavity.Pulmonary interstitial hyperplasia and neutrophils exudation could be seen.2.To explore the protective effect of ethyl pyruvate on high-altitude pulmonary edema?1?Detection of levels of inflammatory factors in serum by ELISACompared with the Control group,the levels of serum IL-6,IL-1? and TNF-? in the H3 d group were significantly higher than those in the Control group?P<0.01?.The levels of IL-6,IL-1? and TNF-? were decreased in EP 1mg/kg group and 5mg/kg group?P<0.01?.Changes were more significant in EP 10mg/kg group?P <0.01?.Compared with the Control group,the levels of serum IL-10 in the H3 d group were lower than those in the Control group?P<0.01?.The levels of IL-10 in serum of EP 1mg/kg group and 5mg/kg group were higher than those in control group?P<0.01?.The levels of IL-10 in EP 10 mg/kg group increased more significantly?P<0.01?.?2?Morphological observationThe histological changes of lung tissue have shown that the pathological changes of HAPE were observed in the lung tissue of the H3 d group.Microscopic observation showed pulmonary telangiectasia,pulmonary interstitial hyperplasia and inflammatory cell infiltration in the alveolar cavity.After treatment with EP,with the increase of EP dose,compared with the H3 d group,the pathological changes in EP 1mg/kg,5mg/kg,10mg/kg group have been gradually improved.The expansion of the capillaries was reduced,inflammatory cell infiltration disappeared,and pulmonary edema has been improved.?3?Expression of p65,IL-6,COX-2 and STAT3 in lung tissue detected by Western blotWestern blot and gray scale analysis have shown that the expressions of p65,IL-6,COX-2 and STAT3 in lung tissue of H3 d group were significantly i ncreased compared with Control group?P<0.01?.After injection with EP 1mg/kg,5 mg/kg and 10mg/kg,expression of p65,IL-6,COX-2,STAT3 were decr eased gradually?P<0.01?,among which EP 10mg/kg group decreased most si gnificantly?P<0.01?.ConclusionsAcute hypoxia can significantly alter oxidative stress condition in rats.E thyl pyruvate have a protective effect on experimental high-altitude pulmonary edema in rats.It may inhibit releasing inflammatory cytokines mediated by NF-?B and STAT-signaling pathway.