Melatonin induced suppression of ER stress and mitochondrial dysfunction inhibited NLRP3 inflammasome activation in COPD mice

In recent decades, the occurrence of chronic obstructive pulmonary disease (COPD) has been increased remarkably in the population. Cigarette smoke (Cs) plays one of the key roles for COPD development. In our study, we explored the ameliorative role of melatonin on COPD progression by using a Cs inhaled in vivo COPD and cigarette smoke extract (CSE)-treated in vitro L-132 (alveolar epithelial cell) models. Mice exposed to Cs (4hr/day for 4 weeks) exhibited abrupt increase of lactate dehydrogenase (LDH) level in broncho alveolar lavage fluid (BALE) and disrupted alveolar structure in lung tissue. Additionally, increased reactive oxygen species (ROS), decreased cellular antioxidant status with reduced GSH/GSSG ratio were also found in Cs exposed lung. Besides, Cs induced endoplasmic reticulum (ER) stress and mitochondrial dysfunctions causing the activation of NLRP3 inflammasome. Activated NLRP3 inflammasome caused Caspase-1 mediated release of IL-1 beta and IL-18 resulting in inflammatory outburst. Melatonin showed protection against COPD both in vitro and in vivo. Exhibiting its anti-inflammatory potential, melatonin also attenuated the lung inflammation. It activated the intracellular antioxidant Thioredoxin-1 (thereby suppressing the TXNIP/NLRP3 pathway) and inhibited the impaired mitophagy mediated inflammasome activation (upregulating PINK-1, Parkin, LC3B-II expression). Melatonin also improved the overall antioxidant status of the COPD lung via NRF-2-HO-1 axis restoration.