Exploring the metabolic phenotypes associated with different host inflammation of acute respiratory distress syndrome (ARDS) from lung metabolomics in mice
Exploring the metabolic phenotypes associated with different host inflammation of acute respiratory distress syndrome (ARDS) from lung metabolomics in mice
复制标题
从小鼠肺代谢组学中探索与急性呼吸窘迫综合征（ARDS）不同宿主炎症相关的代谢表型
DOI：
10.1002/rcm.8971
复制
发表时间：
2021-01-30
影响因子：
2
通讯作者：
Lin, Shi-hui
中科院分区：
文献类型：
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作者：
Yu, Feng;Zhu, Jing;Lin, Shi-hui
本研究的目的是分析急性呼吸窘迫综合征（ARDS）不同宿主炎症的肺代谢组学，以鉴定在不同炎症条件下预测严重程度的生物标志物。方法采用盲肠结扎穿孔（CLP）加脂多糖（LPS）注射致大鼠急性肺损伤（ALI）模型。采用小鼠模型研究ALI/ARDS的肺代谢组学生物标志物。脾切除术模型被用作区分高炎症和低炎症亚型的辅助方法。在CLP/LPS后从小鼠收集血浆、肺组织和支气管肺泡灌洗液（BALF）样品。评估肺损伤的严重程度。采用酶联免疫吸附试验（ELISA）和聚合物链反应（PCR）检测小鼠血清和肺组织中肿瘤坏死因子-α（TNF-α）的表达。计数BALF中的多形核细胞。采用气相色谱/质谱联用（GC/MS）检测肺代谢产物，并利用KEGG数据库预测代谢途径。结果LPS/CLP-Splen组肺损伤较相应的ALI组严重，CLP-Splen组较LPS-Splen组严重。LPS或CLP后血清和肺组织中TNF-α表达显著升高，LPS/CLP-Splen组高于相应的ALI组。CLP‐脾组TNF‐α水平显著高于LPS‐脾组。这两组还显示肺内有显著的中性粒细胞渗出。在差异性炎症过程中，CLP组ALI小鼠肺组织中检测到的差异性代谢产物比LPS组多。在CLP和CLP-Splen组的肺中共检测到41种化合物。相反，在LPS和LPS-Splen组的肺中检测到8种化合物。LPS-脾和CLP-脾组在肺中具有显著的中性粒细胞渗出。肺靶向代谢组学数据的随机森林分析表明，4-羟基苯乙酸、1-氨基环戊烷羧酸（ACPC）、顺乌头酸和羟基苯甲酸是CLP组中高炎症亚组的强预测因子。此外，通过脾切除术，CLP和LPS组之间的13个差异代谢途径被揭示。结论ARDS的高炎症亚组具有更强的炎症反应和更活跃的肺代谢。结合宿主的炎症背景，代谢组学的生物标志物可以帮助评估ARDS的反应严重程度。
Rationale The aim of this study was to analyze the metabolomics of lung with different host inflammation of acute respiratory distress syndrome (ARDS) for the identification of biomarkers for predicting severity under different inflammatory conditions. Methods Cecal ligation and puncture (CLP) and lipopolysaccharide (LPS)‐intratracheal injection induced acute lung injury (ALI) were used. A mouse model was used to explore lung metabolomic biomarkers in ALI/ARDS. The splenectomy model was used as an auxiliary method to distinguish between hyper‐ and hypo‐inflammatory subtypes. Plasma, lung tissue and bronchoalveolar lavage fluid (BALF) samples were collected from mice after CLP/LPS. The severity of lung injury was evaluated. Expression of tumor necrosis factor‐α (TNF‐α) in mice serum and lung was tested by enzyme‐linked immunosorbent assay (ELISA) and polymer chain reaction (PCR). Polymorphonuclear cells in BALF were counted. The lung metabolites were detected by gas chromatography/mass spectrometry (GC/MS), and the metabolic pathways predicted using the KEGG database. Results The LPS/CLP‐Splen group had more severe lung injury than the corresponding ALI group; that in the CLP‐Splen group was more serious than in the LPS‐Splen group. TNF‐α expression was significantly elevated in the serum and lung tissue after LPS or CLP, and higher in the LPS/CLP‐Splen group than in the corresponding ALI group. The level of TNF‐α in the CLP‐Splen group was elevated significantly over that in the LPS‐Splen group. Both these groups also showed significant neutrophil exudation within the lungs. During differential inflammation, more differential metabolites were detected in the lungs of the CLP group ALI mice than in the LPS group. A total of 41 compounds were detected in the lungs of the CLP and CLP‐Splen groups. Contrastingly, eight compounds were detected in the lungs of the LPS and LPS‐Splen groups. The LPS‐Splen and CLP‐Splen groups had significant neutrophil exudation in the lung. Random forest analysis of lung‐targeted metabolomics data indicated 4‐hydroxyphenylacetic acid, 1‐aminocyclopentanecarboxylic acid (ACPC), cis‐aconitic acid, and hydroxybenzoic acid as strong predictors of the hyper‐inflammatory subgroup in the CLP group. Furthermore, with splenectomy, 13 differential metabolic pathways between the CLP and LPS groups were revealed. Conclusions Hyper‐inflammatory subgroups of ARDS have a greater inflammatory response and a more active lung metabolism. Combined with the host inflammation background, biomarkers from metabolomics could help evaluate the response severity of ARDS.