【Abstract】
Background: There is a dearth of drug therapies available for the treatment of acute respiratory distress syndrome (ARDS). Certain metabolites play a key role in ARDS and could serve as potential targets for developing therapies against this respiratory disorder. The present study was designed to determine such 「functional metabolites」 in ARDS using metabolomics and in vivo experiments in a mouse model.
Methods: Metabolomic profiles of blood plasma from 42 ARDS patients and 28 healthy controls were captured using Ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) assay. Univariate and multivariate statistical analysis were performed on metabolomic profiles from blood plasma of ARDS patients and healthy controls to screen for 「functional metabolites」, which were determined by variable importance in projection (VIP) scores and P value. Pathway analysis of all the metabolites was performed. The mouse model of ARDS was established to investigate the role of 「functional metabolites」 in the lung injury and mortality caused by the respiratory disorder.
Results: The metabolomic profiles of patients with ARDS were significantly different from healthy controls, difference was also observed between metabolomic profiles of the non-survivors and the survivors among the ARDS patient pool. Levels of Phenylalanine, D-Phenylalanine and Phenylacetylglutamine were significantly increased in non-survivors compared to the survivors of ARDS. Phenylalanine metabolism was the most notably altered pathway between the non-survivors and survivors of ARDS patients. In vivo animal experiments demonstrated that high levels of Phenylalanine might be associated with the severer lung injury and increased mortality of ARDS.
Conclusion: Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma Phenylalanine.
【中文摘要】
目的:目前針對急性呼吸窘迫症候群(Acute respiratory distress syndrome,ARDS)特異性的靶向治療藥物缺乏。某些代謝產物在ARDS中發揮關鍵性作用,並有可能成為藥物幹預的靶點。因此本文旨在通過代謝組學和小鼠體內實驗確定這類「功能性代謝產物」在ARDS中的作用。
方法:採用超高效液相色譜串聯質譜(UHPLC-MS/MS)分析42個ARDS患者和28個健康志願者血清的代謝組學。運用單因素和多因素綜合分析獲得不同代謝產物的變量差異貢獻度評分(VIP)以及P值,確定「功能性的代謝產物」。同時對所有代謝產物進行通路分析。最後,在ARDS小鼠模型中探究「功能性代謝物」的作用。
結果:ARDS患者的代謝組學特徵與健康對照組有顯著差異,ARDS患者中死亡組和存活組的代謝組學特徵也存在差異。與ARDS存活組相比,死亡組的苯丙氨酸(Phenylalanine)、D-苯丙氨酸(D-Phenylalanine)和苯乙醯穀氨醯胺( Phenylacetylglutamine)水平顯著升高。苯丙氨酸代謝是ARDS患者死亡組和存活組之間改變最顯著的差異代謝通路。此外,體內動物實驗表明,苯丙氨酸可加重ARDS的肺損傷程度並且增加小鼠死亡率。
結論:血清苯丙氨酸含量的升高可能導致急性呼吸窘迫症候群的死亡率增加 。