Inhibition of PAD2 Improves Survival in a Mouse Model of Lethal LPS-Induced Endotoxic Shock
Authors
Wu, ZhenyuDeng, Qiufang
Pan, Baihong
Alam, Hasan B.
Tian, Yuzi
Bhatti, Umar F.
Liu, Baoling
Mondal, Santanu
Thompson, Paul R
Li, Yongqing
Document Type
Journal ArticlePublication Date
2020-08-01Keywords
LPS-induced endotoxic shockNETosis
PAD2
acute lung injury
selective PAD2 inhibitor
Amino Acids, Peptides, and Proteins
Biochemistry, Biophysics, and Structural Biology
Enzymes and Coenzymes
Pathological Conditions, Signs and Symptoms
Metadata
Show full item recordAbstract
Endotoxemia induced by lipopolysaccharide (LPS) is an extremely severe syndrome identified by global activation of inflammatory responses. Neutrophil extracellular traps (NETs) play an important role in the development of endotoxemia. Histone hypercitrullination catalyzed by peptidylarginine deiminases (PADs) is a key step of NET formation. We have previously demonstrated that simultaneous inhibition of PAD2 and PAD4 with pan-PAD inhibitors can decrease NETosis and improve survival in a mouse model of LPS-induced endotoxic shock. However, the effects of PAD2 specific inhibition during NETosis and endotoxic shock are poorly understood. Therefore, in the present study, we aimed to investigate the effect of the specific PAD2 or PAD4 inhibitor on LPS-induced endotoxic shock in mice. We found that PAD2 inhibition but not PAD4 inhibition improves survival. Also, the levels of proinflammatory cytokines and NETosis were significantly reduced by PAD2 inhibitor. To our knowledge, this study demonstrates for the first time that PAD2 inhibition can reduce NETosis, decrease inflammatory cytokine production, and protect against endotoxin-induced lethality. Our findings provided a novel therapeutic strategy for the treatment of endotoxic shock.Source
Wu Z, Deng Q, Pan B, Alam HB, Tian Y, Bhatti UF, Liu B, Mondal S, Thompson PR, Li Y. Inhibition of PAD2 Improves Survival in a Mouse Model of Lethal LPS-Induced Endotoxic Shock. Inflammation. 2020 Aug;43(4):1436-1445. doi: 10.1007/s10753-020-01221-0. PMID: 32239392. Link to article on publisher's site
DOI
10.1007/s10753-020-01221-0Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29500PubMed ID
32239392Related Resources
ae974a485f413a2113503eed53cd6c53
10.1007/s10753-020-01221-0