L-Arginine, as an Important Metabolic Biomarker, Participates in the Pathological Process of Chronic Obstructive Pulmonary Disease

Aim: Chronic obstructive pulmonary disease (COPD) is one of the most widespread diseases, its pathogenesis is very complex and unclear. The purpose of this study was to find the new biomarkers of COPD and elucidate its role in the pathogenesis and treatment of COPD. Methods: 221 patients with COPD and 60 healthy people were enrolled in the study. Non-targeted analysis of metabolites in plasma of COPD patients and healthy people were performed by ultra-high performance liquid chromatography (UPLC) and quadrupole time-of-flight mass spectrometry (TOF-MS). The differential metabolites were analyzed and identified by multivariate analysis between healthy people and COPD patients. The role and mechanisms of the differential metabolic biomarkers in COPD were investigated and verified with COPD rats, arginosuccinate synthetase 1(ASS-l) KO mice and bronchial epithelial cells (BECs) in vivo and in vitro. Meanwhile, whether the differential biomarkers can be the potential treatment targets for COPD was also investigated. Results: 85 differentials metabolites were identified between healthy people and COPD patients by metabonomics. L-arginine (LA) was the most obvious differential metabolite among the 85 metabolites. At the same time, it was found that LA had protective effects on COPD with in vivo and in vitro experiments. Silencing ASS-1, which regulates LA metabolism, and α-methy-DL-aspartic (NHLA), an ASS-1 inhibitor, canceled the protective effect of LA on COPD. The mechanism of LA in COPD was related to the inhibition of ROS/NLRP3/NF-κB signaling pathway. Conclusion: L-arginine (LA) as a key metabolic marker is identified in COPD patients. LA has a protective effect on COPD, its mechanism is related to the regulation of ROS/NLRP3/NF-κB signaling pathway. LA may be a novel target for the treatment of COPD. Funding Information: This research was supported by National Natural Science Foundation of China (81400800). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: All patient experiments were performed under the guidance of the Helsinki Declaration and approved by the Research Council of Affiliated Nanjing Hospital of Nanjing University of Chinese Medicine (KY2017019). All animal experiments were performed in accordance with the principles of the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publications, eighth edition, 2011) and were approved by the Research Council and Animal Care and Use Committee of Affiliated Nanjing Hospital of Nanjing University of Chinese Medicine and Army Medical Center, Army Medical University.