Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome

• Published in: Journal of pineal research Vol. 60; no. 4; pp. 405 - 414
• Main Authors: Zhang, Yong, Li, Xiru, Grailer, Jamison J., Wang, Na, Wang, Mingming, Yao, Jianfei, Zhong, Rui, Gao, George F., Ward, Peter A., Tan, Dun-Xian, Li, Xiangdong
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2016
• Subjects: acute lung injury; Acute Lung Injury - metabolism; Acute Lung Injury - pathology; Animals; Anti-Inflammatory Agents - pharmacology; Blotting, Western; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; histone; Inflammasomes - drug effects; Inflammasomes - metabolism; Macrophages - drug effects; Male; melatonin; Melatonin - pharmacology; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP inflammasome; reactive oxygen species; Reactive Oxygen Species - metabolism; X-Ray Microtomography; NLRP inflammasome; histone; melatonin; acute lung injury; reactive oxygen species
• ISSN: 0742-3098; 1600-079X
• DOI: 10.1111/jpi.12322

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration–approved drug therapies. Melatonin is a well‐known anti‐inflammatory molecule, which has proven to be effective in ALI induced by many conditions. Emerging studies suggest that the NLRP3 inflammasome plays a critical role during ALI. How melatonin directly blocks activation of the NLRP3 inflammasome in ALI remains unclear. In this study, using an LPS‐induced ALI mouse model, we found intratracheal (i.t.) administration of melatonin markedly reduced the pulmonary injury and decreased the infiltration of macrophages and neutrophils into lung. During ALI, the NLRP3 inflammasome is significantly activated with a large amount of IL‐1β 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. Notably, i.t. route of melatonin administration opens a more efficient therapeutic approach for treating ALI.