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    Inhibition of PAD2 Improves Survival in a Mouse Model of Lethal LPS-Induced Endotoxic Shock

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    Authors
    Wu, Zhenyu
    Deng, Qiufang
    Pan, Baihong
    Alam, Hasan B.
    Tian, Yuzi
    Bhatti, Umar F.
    Liu, Baoling
    Mondal, Santanu
    Thompson, Paul R
    Li, Yongqing
    UMass Chan Affiliations
    Thompson Lab
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Journal Article
    Publication Date
    2020-08-01
    Keywords
    LPS-induced endotoxic shock
    NETosis
    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
    
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    Link to Full Text
    https://doi.org/10.1007/s10753-020-01221-0
    Abstract
    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/s10753-020-01221-0
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/29500
    PubMed ID
    32239392
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    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1007/s10753-020-01221-0
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