PMID- 31428103
OWN - NLM
STAT- MEDLINE
DCOM- 20201013
LR  - 20201013
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 10
DP  - 2019
TI  - The Caspase Inhibitor Z-VAD-FMK Alleviates Endotoxic Shock via Inducing 
      Macrophages Necroptosis and Promoting MDSCs-Mediated Inhibition of Macrophages 
      Activation.
PG  - 1824
LID - 10.3389/fimmu.2019.01824 [doi]
LID - 1824
AB  - Macrophages play a critical role in the pathogenesis of endotoxin shock by 
      producing excessive amounts of pro-inflammatory cytokines. A pan-caspase 
      inhibitor, zVAD, can be used to induce necroptosis under certain stimuli. The 
      role of zVAD in both regulating the survival and activation of macrophages, and 
      the pathogenesis of endotoxin shock remains not entirely clear. Here, we found 
      that treatment of mice with zVAD could significantly reduce mortality and 
      alleviate disease after lipopolysaccharide (LPS) challenge. Notably, in 
      LPS-challenged mice, treatment with zVAD could also reduce the percentage of 
      peritoneal macrophages by promoting necroptosis and inhibiting pro-inflammatory 
      responses in macrophages. In vitro studies showed that pretreatment with zVAD 
      promoted LPS-induced nitric oxide-mediated necroptosis of bone marrow-derived 
      macrophages (BMDMs), leading to reduced pro-inflammatory cytokine secretion. 
      Interestingly, zVAD treatment promoted the accumulation of myeloid-derived 
      suppressor cells (MDSCs) in a mouse model of endotoxin shock, and this process 
      inhibited LPS-induced pro-inflammatory responses in macrophages. Based on these 
      findings, we conclude that treatment with zVAD alleviates LPS-induced endotoxic 
      shock by inducing macrophage necroptosis and promoting MDSC-mediated inhibition 
      of macrophage activation. Thus, this study provides insights into the effects of 
      zVAD treatment in inflammatory diseases, especially endotoxic shock.
FAU - Li, Xuehui
AU  - Li X
AD  - Cheeloo College of Medicine, Shandong University, Jinan, China.
FAU - Yao, Xiaoying
AU  - Yao X
AD  - Institute of Immunology and Molecular Medicine, Jining Medical University, 
      Jining, China.
FAU - Zhu, Yuzhen
AU  - Zhu Y
AD  - Institute of Immunology and Molecular Medicine, Jining Medical University, 
      Jining, China.
FAU - Zhang, Hui
AU  - Zhang H
AD  - Institute of Immunology and Molecular Medicine, Jining Medical University, 
      Jining, China.
FAU - Wang, Haiyan
AU  - Wang H
AD  - Institute of Immunology and Molecular Medicine, Jining Medical University, 
      Jining, China.
FAU - Ma, Qun
AU  - Ma Q
AD  - Institute of Immunology and Molecular Medicine, Jining Medical University, 
      Jining, China.
FAU - Yan, Fenglian
AU  - Yan F
AD  - Institute of Immunology and Molecular Medicine, Jining Medical University, 
      Jining, China.
FAU - Yang, Yonghong
AU  - Yang Y
AD  - Department of Central Laboratory, Affiliated Hospital of Jining Medical 
      University, Jining, China.
FAU - Zhang, Junfeng
AU  - Zhang J
AD  - Institute of Immunology and Molecular Medicine, Jining Medical University, 
      Jining, China.
FAU - Shi, Hui
AU  - Shi H
AD  - Institute of Immunology and Molecular Medicine, Jining Medical University, 
      Jining, China.
FAU - Ning, Zhaochen
AU  - Ning Z
AD  - Institute of Immunology and Molecular Medicine, Jining Medical University, 
      Jining, China.
FAU - Dai, Jun
AU  - Dai J
AD  - Institute of Immunology and Molecular Medicine, Jining Medical University, 
      Jining, China.
FAU - Li, Zhihua
AU  - Li Z
AD  - Institute of Immunology and Molecular Medicine, Jining Medical University, 
      Jining, China.
FAU - Li, Chunxia
AU  - Li C
AD  - Institute of Immunology and Molecular Medicine, Jining Medical University, 
      Jining, China.
FAU - Su, Fei
AU  - Su F
AD  - Institute of Animal Husbandry and Veterinary Sciences, Zhejiang Academy of 
      Agricultural Sciences, Hangzhou, China.
FAU - Xue, Yin
AU  - Xue Y
AD  - Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China.
FAU - Meng, Xiangzhi
AU  - Meng X
AD  - Department of Microbiology, Immunology, and Molecular Genetics, University of 
      Texas Health Science Center at San Antonio, San Antonio, TX, United States.
FAU - Dong, Guanjun
AU  - Dong G
AD  - Institute of Immunology and Molecular Medicine, Jining Medical University, 
      Jining, China.
FAU - Xiong, Huabao
AU  - Xiong H
AD  - Department of Medicine, Icahn School of Medicine at Mount Sinai, Precision 
      Immunology Institute, New York, NY, United States.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190802
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Amino Acid Chloromethyl Ketones)
RN  - 0 (Caspase Inhibitors)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Amino Acid Chloromethyl Ketones/*pharmacology
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Caspase Inhibitors/*pharmacology
MH  - Caspases/metabolism
MH  - Female
MH  - Lipopolysaccharides/pharmacology
MH  - Macrophage Activation/*drug effects
MH  - Macrophages, Peritoneal/*drug effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Myeloid-Derived Suppressor Cells/*drug effects/metabolism
MH  - Necroptosis/*drug effects
MH  - Shock, Septic/*drug therapy/metabolism
PMC - PMC6687755
OTO - NOTNLM
OT  - MDSCs
OT  - endotoxin shock
OT  - macrophage
OT  - necroptosis
OT  - zVAD
EDAT- 2019/08/21 06:00
MHDA- 2020/10/21 06:00
PMCR- 2019/01/01
CRDT- 2019/08/21 06:00
PHST- 2019/03/23 00:00 [received]
PHST- 2019/07/18 00:00 [accepted]
PHST- 2019/08/21 06:00 [entrez]
PHST- 2019/08/21 06:00 [pubmed]
PHST- 2020/10/21 06:00 [medline]
PHST- 2019/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2019.01824 [doi]
PST - epublish
SO  - Front Immunol. 2019 Aug 2;10:1824. doi: 10.3389/fimmu.2019.01824. eCollection 
      2019.