| BackgroundAcute lung injury(ALI)is a severe inflammatory reaction caused by various intrapulmonary(direct injury)or extrapulmonary(indirect injury)factors,resulting in varying degrees of damage to the structure of the lung.The clinical manifestation is progressive hypoxic respiratory insufficiency,accompanied by imaging changes of bilateral lung infiltration,and the mortality rate is as high as 45%.It is a common disease in intensive care unit.There are many causes and high risk factors of ALI,and pulmonary infection is the main cause of ALI.In humans,the basic pathophysiological mechanisms of ALI include excessive inflammatory response,reduced lung volume,decreased lung compliance,destruction of alveolar-capillary barrier and imbalance of ventilation / blood flow ratio.Histologically,it showed A)neutrophil alveolitis,B)intraalveolar hyaline membrane deposition,and C)microvascular thrombosis,indicating coagulation cascade activation and endothelial injury.There is no specific drug treatment for patients with ALI.In the current field of prevention and treatment of ALI,the efficacy of corticosteroid steroid use remains controversial.Different pathogenic factors,timing,dosage and course of treatment have different pharmacological effects and therapeutic effects on ALI.Studies have shown that high doses of corticosteroids can not benefit ALI patients,and even increase the incidence of systemic infection.On the other hand,low-dose dexamethasone can show better anti-inflammatory effect,play a lung protective role in ALI,and may improve the morbidity and mortality of patients.However,the study of low-dose dexamethasone on the intervention effect of ALI only focused on the changes of inflammatory mediators and cell function,and failed to grasp the changes of life and the direction of inflammatory outcome as a whole.Metabolites are small molecular compounds that can dynamically reflect changes in the state of the body.Metabonomics is a subject that studies the types,quantities and changes of metabolites of disturbed organisms,and plays an important role in exploring potential biomarkers and drug treatment targets of diseases.In the field of lung diseases,metabonomics has been used to explore the pathogenesis,early diagnosis and drug efficacy of COVID-19,lung cancer,asthma,chronic obstructive pneumonia,pulmonary fibrosis and so on.Therefore,using metabonomics to explore the changes of metabolic spectrum of life in Sigma-LPS-induced ALI rats and ALI rats after early intervention with low-dose dexamethasone is of great significance to find biomarkers for the formation and outcome of ALI.ObjectivesThe metabolic spectrum changes of ALI rats and early low-dose dexamethasone-treated ALI rats were observed by non-targeted metabonomics technique,in order to find biomarkers or therapeutic targets for ALI formation and outcome.Methods1、Eighteen healthy adult male SD rats were randomly divided into control group(n= 6),sham operation group(n = 6)and model group(n = 6).The rats in the control group did not receive any treatment,the rats in the sham operation group were disinfected and sutured only after exposing the trachea,and the rats in the experimental group were given LPS(10mg/kg,10mg/m L)by exposed trachea,and those with less than 0.2m L were balanced with normal saline.The rats in each group were routinely fed for 24 hours,and the blood of inferior vena cava was taken for detection of inflammatory factors,bronchoalveolar lavage fluid for inflammatory factors and total protein concentration,left upper lobe for HE staining and left lower lobe to calculate lung wet-dry ratio.2、24 adult male healthy SD rats were randomly divided into control group(n = 8),model group(n = 8)and low dose dexamethasone intervention group(n = 8).The model group and the low-dose dexamethasone intervention group were treated with exposed intratracheal instillation of LPS solvent.One hour after the infusion,the rats in the low-dose dexamethasone intervention group were injected intraperitoneally with dexamethasone,while the control group and the model group were injected with the normal saline for trim.After 24 hours of routine feeding,the blood of inferior vena cava was taken to detect inflammatory factors and metabonomics,and the bronchoalveolar lavage fluid was used to detect the concentration of inflammatory factors and total protein.Finally,the lung tissue was obtained,and the wet-to-dry ratio of the left lower lobe was calculated,and the left upper lobe was stained with HE.3、The obtained rat plasma samples were tested by metabonomics,and the analysis platform was established after data preprocessing.The differential metabolites were screened and analyzed,and the metabolic map was drawn.Finally,the biological explanation was given.Results1.After exposed intratracheal instillation of LPS at the concentration of 10mg/m L for24 hours according to the standard of 10mg/kg,a stable animal model of ALI could be formed.2.The metabonomic results were analyzed according to the criteria of p < 0.05 and |log2FC | ≥ 0.26.Finally,19 coregulated differentially expressed metabolites were screened.3.KEGG pathway enrichment showed that differential metabolites were mainly involved in sphingomyelin metabolism,arachidonic acid metabolism,linolenic acid and linoleic acid metabolism,phospholipid biosynthesis,fatty acid metabolism,arginine and proline metabolism,tryptophan metabolism,carnitine synthesis and mitochondrialβ-oxidation of long-chain saturated fatty acids.4.The results showed that 12 HETE,dihydrosphingosine,proline and N2-acetylornithine may be potential biomarkers for the formation,outcome and prognosis of ALI,which are mainly involved in sphingomyelin metabolism,arachidonic acid metabolism,arginine and proline metabolism.ALOX5 and ALOX12 may be potential targets for the treatment of acute lung injury.Conclusion12HETE,dihydrosphingosine,proline and N2-acetylornithine may be potential biomarkers for the formation,prognosis and prognosis of ALI,which are mainly related to sphingomyelin metabolism,arachidonic acid metabolism,arginine and proline metabolism.ALOX5 and ALOX12 may be potential targets for ALI therapy. |
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