Blockage of P2X7 attenuates acute lung injury in mice by inhibiting NLRP3 inflammasome.
NLRP3 inflammasome is engaged in the inflammatory response during acute lung injury (ALI). Purinergic receptor P2X7 has been reported to be upstream of NLRP3 activation. However, the therapeutic implication of P2X7 in ALI remains to be explored. The present study used lipopolysaccharide (LPS)-induced mouse model to investigate the therapeutic potential of P2X7 blockage in ALI. Our results showed that P2X7/NLRP3 inflammasome pathway was significantly upregulated in the lungs of ALI mice as compared with control mice. P2X7 antagonist A438079 suppressed NLRP3/ASC/caspase 1 activation, production of IL-1β, IL-17A and IFN-γ and neutrophil infiltration but not the production of IL-10, resulting in a significant amelioration of lung injury. Moreover, blockage of P2X7 significantly inhibited NLRP3 inflammasome activation and IL-1β production in bone marrow derived macrophages. Similar results were obtained using another P2X7 inhibitor brilliant blue G (BBG) in vivo. Thus, pharmacological blockage of P2X7/NLRP3 pathway can be considered as a potential therapeutic strategy in patients with ALI.
Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, China.
Shuang
S
Wang
Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, China.
Jijun
J
Zhao
Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, China.
Hongyue
H
Wang
Department of Pathology, First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, China.
Yingjie
Y
Liang
Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, China.
Niansheng
N
Yang
Department of Pediatrics, First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, China. Electronic address: zsuhyf@163.com.
Yuefang
Y
Huang
D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D058920:Purinergic P2X Receptor Antagonists / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D013777:Tetrazoles / Q000008:administration & dosage / Q000009:adverse effects
C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; D002352:Carrier Proteins; D016207:Cytokines; D058847:Inflammasomes; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles
Acute lung injury; IL-1β; Inflammasome; Neutrophils; P2X7