Melatonin prevents lung injury by regulating apelin 13 to improve mitochondrial dysfunction

Lu Zhang,Rui Yang,Hongli Shan,Huitong Shan,Yingying Guo,Tongzhu Jin,Xiaomin Su,Haihai Liang,Yining Wang,Ruonan Fang,Yue Li,Xiaoguang Zhao,Fang Li

doi:10.1038/s12276-019-0273-8

Abstract

Pulmonary fibrosis is a progressive disease characterized by epithelial cell damage, fibroblast proliferation, excessive extracellular matrix (ECM) deposition, and lung tissue scarring. Melatonin, a hormone produced by the pineal gland, plays an important role in multiple physiological and pathological responses in organisms. However, the function of melatonin in the development of bleomycin-induced pulmonary injury is poorly understood. In the present study, we found that melatonin significantly decreased mortality and restored the function of the alveolar epithelium in bleomycin-treated mice. However, pulmonary function mainly depends on type II alveolar epithelial cells (AECIIs) and is linked to mitochondrial integrity. We also found that melatonin reduced the production of reactive oxygen species (ROS) and prevented apoptosis and senescence in AECIIs. Luzindole, a nonselective melatonin receptor antagonist, blocked the protective action of melatonin. Interestingly, we found that the expression of apelin 13 was significantly downregulated in vitro and in vivo and that this downregulation was reversed by melatonin. Furthermore, ML221, an apelin inhibitor, disrupted the beneficial effects of melatonin on alveolar epithelial cells. Taken together, these results suggest that melatonin alleviates lung injury through regulating apelin 13 to improve mitochondrial dysfunction in the process of bleomycin-induced pulmonary injury.

Highlights

Direct or indirect stimulating factors lead to the diffuse alveolar damage, which increased alveolar capillary membrane permeability, excessive pulmonary inflammation, and alveolar epithelial cell apoptosis termed lung injury
In the present study, we firstly clarified that the protective effect of MLN on lung injury is mediated via the prevention of reactive oxygen species (ROS) generation, apoptosis and senescence
The beneficial effect of MLN depends on mitochondrial function by regulating apelin 13

Summary

Introduction

Direct or indirect stimulating factors lead to the diffuse alveolar damage, which increased alveolar capillary membrane permeability, excessive pulmonary inflammation, and alveolar epithelial cell apoptosis termed lung injury. Excessive apoptosis of type II alveolar epithelial cells (AECIIs) impairs the epithelial barrier[1], accompanied by the development of senescence and Mitochondrial dysfunction and reactive oxygen species (ROS) overproduction have been proposed to mediate the pathogenesis of many diseases, including lung injury[3,4]. Suplatast tosilate protected against hyperoxic lung injury by decreasing the degree of oxidative stress induced by ROS, through its ability to scavenge hydroxyl radicals[6]. It is urgent to explore new effective methods for regulating mitochondrial function to ameliorate lung injury

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