Melatonin Alleviates Acute Lung Injury Through Inhibiting The NLRP3 Inflammasome In Mouse

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is the symptoms of acute progressive respiratory insufficiency or respiratory failure which usually caused by the trauma, blood transfusion, infection and other factors. ALI is a common clinical syndrome characterized by pulmonary edema, pulmonary hemorrhage and severely damaged respiratory function. In spite of considerable effort, the mortality remains high (35%-40%) and there is still no Food and Drug Administration approved treatment for ALI/ARDS. Melatonin (N-acetyl-5-methoxytryptamine) is synthesized by the pineal gland in mammals, and also by other non-endocrine organs such as the Harderian gland, skin, gut and the immune system. Melatonin is a well-known anti-inflammatory molecule, which has proven to be effective in ALI induced by many conditions. However the precise mechanism remains unclear. The NLRP3 inflammasome is a multi-protein complex of the innate immune system. Once activated, NLRP3 recruits the adapter ASC (apoptosis-related speck-like protein containing a caspase recruitment domain), which in turn recruits procaspase-1. Procaspase-1 autocatalyzes its cleavage and activation, resulting in maturation of the precursor forms of interleukin IL-β and IL-18 into active proinflammatory cytokines and initiation of pyroptotic cell death. Emerging studies suggest that the NLRP3 inflammasome plays a critical role during ALI. Whereas activation of the NLRP3 inflammasome can help host defense against invading bacteria and pathogens, excessive activation of the inflammasome can lead to inflammation-associated tissue injury. How melatonin directly blocks activation of the NLRP3 inflammasome in ALI remains unclear.In this study, we firstly established a mouse model of ALI induced by LPS. In contrast to systemical delivery, we found that intratracheal instillation of melatonin was more effective for improving ALI pathology, such as the lung pathology, body weight and temperature loss. Notably, nebulised melatonin could be an efficient therapeutic strategy for ALI. During the early stage of ALI, the NLRP3 inflammasome is significantly activated with a large amount of IL-1(3 and the activated caspase-1 occurring in the lung. Melatonin inhibits the activation of the NLRP3 inflammasome by both suppressing the release of extracellular histones and directly blocking histone-induced NLRP3 inflammasome activation. Futhermore, we found the inhibition function of melatonin is not mediated by inhibiting the ROS and may be mediated by blocking the function of calmodulin. We also explored the potent therapeutic effect of melatonin for influenza virus-induced ALI, however, the results was disappointing. Since the complicated interaction between host and influenza virus, the dose and medication occasion of melatonin needs to be further explored.In conclusion, melatonin can improve the severity of LPS-induced ALI via blocking activation of the NLRP3 inflammasome. Melatonin reduces the release of extracellular histones as well as directly inhibits NLRP3 inflammasome activation.