Untargeted Metabolomics Reveals Alterations of Rhythmic Pulmonary Metabolism in IPF
Wei Sun,
Jiuqiang Ren,
Zixian Jia,
Puyang Liang,
Shengxi Li,
Meiyue Song,
Yinghao Cao,
Haoran Chen,
Qiang Luo,
Lifeng Yang,
Jing Wang,
Chen Wang,
Lin Wang
Affiliations
Wei Sun
Department of Respiratory and Critical Care, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130012, China
Jiuqiang Ren
State Key Laboratory of Common Mechanism Research for Major Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
Zixian Jia
State Key Laboratory of Common Mechanism Research for Major Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
Puyang Liang
Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Shanghai 200031, China
Shengxi Li
State Key Laboratory of Common Mechanism Research for Major Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
Meiyue Song
State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
Yinghao Cao
State Key Laboratory of Common Mechanism Research for Major Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
Haoran Chen
State Key Laboratory of Common Mechanism Research for Major Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
Qiang Luo
Department of Cardiology, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130012, China
Lifeng Yang
Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Shanghai 200031, China
Jing Wang
State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
Chen Wang
Department of Respiratory and Critical Care, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130012, China
Lin Wang
State Key Laboratory of Common Mechanism Research for Major Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive condition characterized by the impairment of alveolar epithelial cells. Despite continued research efforts, the effective therapeutic medication is still absent due to an incomplete understanding of the underlying etiology. It has been shown that rhythmic alterations are of significant importance in the pathophysiology of IPF. However, a comprehensive understanding of how metabolite level changes with circadian rhythms in individuals with IPF is lacking. Here, we constructed an extensive metabolite database by utilizing an unbiased reference system culturing with 13C or 15N labeled nutrients. Using LC-MS analysis via ESI and APCI ion sources, 1300 potential water-soluble metabolites were characterized and applied to evaluate the metabolic changes with rhythm in the lung from both wild-type mice and mice with IPF. The metabolites, such as glycerophospholipids and amino acids, in WT mice exhibited notable rhythmic oscillations. The concentrations of phospholipids reached the highest during the fast state, while those of amino acids reached their peak during fed state. Similar diurnal variations in the metabolite rhythm of amino acids and phospholipids were also observed in IPF mice. Although the rhythmic oscillation of metabolites in the urea cycle remained unchanged, there was a significant up-regulation in their levels in the lungs of IPF mice. 15N-ammonia in vivo isotope tracing further showed an increase in urea cycle activity in the lungs of mice with IPF, which may compensate for the reduced efficiency of the hepatic urea cycle. In sum, our metabolomics database and method provide evidence of the periodic changes in lung metabolites, thereby offering valuable insights to advance our understanding of metabolic reprogramming in the context of IPF.