title: Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome.
abstract: 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.
authors.affiliation: State Key Laboratory of the Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, The 301th Hospital of PLA, Beijing, China.
authors.forename: Xiru
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Jamison J
authors.initials: JJ
authors.lastname: Grailer
authors.affiliation: State Key Laboratory of the Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: State Key Laboratory of the Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Wang
authors.affiliation: State Key Laboratory of the Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Yao
authors.affiliation: State Key Laboratory of the Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhong
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences Beijing, China.
authors.forename: George F
authors.initials: GF
authors.lastname: Gao
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
authors.affiliation: The University of Texas Health Science Center at San Antonio Department of Cellular and Structural Biology, San Antonio, TX, USA.
authors.forename: Dun-Xian
authors.initials: DX
authors.lastname: Tan
authors.affiliation: State Key Laboratory of the Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Li
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D000893:Anti-Inflammatory Agents; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D008550:Melatonin
keywords: NLRP inflammasome; acute lung injury; histone; melatonin; reactive oxygen species