Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma phenylalanine

Jing Xu,Ruoming Tan,Tingting Pan,Jie Wang,Yihui Wang,Xiaoling Qi,Zhaojun Liu,Jialin Liu,Hongping Qu,Yi Zhang,Zheying Tao,Jingjing Zhang,Hong Chen,Xiaoli Wang

doi:10.1186/s12931-020-01364-6

Abstract

BackgroundThere 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.MethodsMetabolomic 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.ResultsThe 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.ConclusionIncreased mortality of acute respiratory distress syndrome was associated with high levels of plasma Phenylalanine.Trial registrationChinese Clinical Trial Registry, ChiCTR1800015930. Registered 29 April 2018, http://www.chictr.org.cn/edit.aspx?pid=25609&htm=4

Highlights

There is a dearth of drug therapies available for the treatment of acute respiratory distress syndrome (ARDS)
The differential metabolomic profiles between the ARDS patients and the healthy controls, and between the survivors and the non-survivors from the patient pool were obtained via Principal Component Analysis (PCA) and Partial Least Square-Discriminant Analysis (PLS-DA)
Significant separation of metabolomic profiles was observed between the survivors and non-survivors of ARDS (Fig. 1b), and PLS-DA served as a valid model for discriminating the metabolites (R2 = 0.89, Q2 = 0.49) (Fig. 1d)

Summary

Introduction

There is a dearth of drug therapies available for the treatment of acute respiratory distress syndrome (ARDS). Previous studies have performed metabolomic analysis of plasma, pulmonary edema fluid and bronchoalveolar lavage fluid (BALF) in ARDS patients, preliminarily results revealed a broad range of metabolites that could help in diagnosis and stratify ARDS [3,4,5,6]. It is still unknown whether there exist any specific metabolites that help in identifying different phenotypes of ARDS and have a crucial function in the disease process. Kentaro Tojo et al have revealed that the enhancement of glycolysis attenuated the lung tissue injury by protecting alveolar epithelial cells from decline in energy [9] Their results indicated that metabolites played an important role in ARDS

Methods

Results

Conclusion