Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of the National Health Commission Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Critical Care Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Front Immunol. 2021 May 4;12:668002. doi: 10.3389/fimmu.2021.668002. eCollection 2021.
It has been reported that melatonin can relieve the symptoms of chronic obstructive pulmonary disease (COPD) by improving sleep quality, that is to say, the pineal secreted hormone melatonin has a protective effect in the pathogenesis of COPD, but its underlying mechanism remains unclear. In this study, we recruited 73 people into control (n = 22), stable COPD (n = 20), and acute exacerbation of COPD (n = 31) groups to detect the serum melatonin levels. Then, through the mouse model, we employed a systematic study based on the metabolomic and transcriptomic analyses to investigate the molecular mechanisms involved in the progression of the disease. Circulating melatonin in acute exacerbation of COPD patients was decreased compared with that in healthy donors and stable COPD patients. The serum melatonin level was positively correlated with lung function parameters, such as FEV1, FEV1/FVC, and FEV1% predicted in acute exacerbation of COPD patients. Animal experiments showed that melatonin can not only alleviate chronic lipopolysaccharide (LPS)-induced mouse lung destruction and chronic lung inflammation but also reduce necroptosis (RIP1/RIP3/MLKL), a programmed cell death process in bronchial epithelial cells. The protective effect of melatonin on chronic lung inflammation was further suggested to be dependent on targeting its membrane receptor MT1/MT2. In addition, transcriptomic and metabolomic profiling in the lungs of mice indicated that LPS can induce perturbations of the mainstream metabolites associated with amino acid and energy metabolism. Melatonin may reduce the necroptosis by modifying the disordered pathways of alanine, aspartate, and glutamate metabolism caused by LPS. This study suggests that melatonin may act as a potential therapeutic agent for alleviating the chronic inflammation associated with COPD.
据报道，褪黑素通过改善睡眠质量可以缓解慢性阻塞性肺疾病（COPD）的症状，也就是说，松果体分泌的激素褪黑素在 COPD 的发病机制中具有保护作用，但具体的作用机制尚不清楚。在这项研究中，我们招募了 73 人进入对照组（n=22）、稳定期 COPD 组（n=20）和 COPD 急性加重组（n=31），以检测血清褪黑素水平。然后，通过小鼠模型，我们采用基于代谢组学和转录组学分析的系统研究，探讨了疾病进展中涉及的分子机制。与健康供体和稳定期 COPD 患者相比，COPD 急性加重患者的循环褪黑素水平降低。急性加重期 COPD 患者的血清褪黑素水平与肺功能参数（如 FEV1、FEV1/FVC 和 FEV1%预测值）呈正相关。动物实验表明，褪黑素不仅可以减轻慢性脂多糖（LPS）诱导的小鼠肺破坏和慢性肺炎症，还可以减少坏死性凋亡（RIP1/RIP3/MLKL），即支气管上皮细胞的一种程序性细胞死亡过程。褪黑素对慢性肺炎症的保护作用进一步表明，它依赖于靶向其膜受体 MT1/MT2。此外，小鼠肺部的转录组学和代谢组学分析表明，LPS 可以诱导与氨基酸和能量代谢相关的主流代谢物紊乱。褪黑素可能通过修饰 LPS 引起的丙氨酸、天冬氨酸和谷氨酸代谢紊乱途径来减少坏死性凋亡。这项研究表明，褪黑素可能作为一种潜在的治疗药物，用于缓解与 COPD 相关的慢性炎症。
