PMID- 32145512
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240227
IS  - 1878-1705 (Electronic)
IS  - 1567-5769 (Linking)
VI  - 82
DP  - 2020 Mar 4
TI  - Dexmedetomidine preconditioning alleviated murine liver ischemia and reperfusion 
      injury by promoting macrophage M2 activation via PPARgamma/STAT3 signaling.
PG  - 106363
LID - S1567-5769(19)32429-4 [pii]
LID - 10.1016/j.intimp.2020.106363 [doi]
AB  - BACKGROUND: Although a protective role of dexmedetomidine in liver ischemia and 
      reperfusion (IR) injury has been reported, the underlying mechanism remains to be 
      determined. The aim of this study is to analyze the effects of dexmedetomidine on 
      the regulation of macrophage innate immune activation during liver IR. METHODS: 
      Mice were randomly divided into dexmedetomidine preconditioning (DEX) and 
      phosphate buffered saline vehicle control (VEH) groups. A murine 70% warm liver 
      IR model was used, and liver injury and intrahepatic inflammation was compared 
      between groups. Bone marrow-derived macrophages (BMDMs) were stimulated with LPS 
      in the presence or absence of dexmedetomidine. The inflammatory cytokine 
      production was measured, and the macrophage M1/M2 polarization was determined in 
      different groups. The underlying mechanism of dexmedetomidine in regulating 
      macrophage M2 activation was also analyzed. RESULTS: Compared to mice observed in 
      the control group, mice in the DEX group showed reduced liver injury and 
      diminished proinflammatory immune responses in livers post IR. In vitro, 
      dexmedetomidine pretreatment promoted BMDMs M2 activation, as evidenced by 
      increased Arg1 and Mrc1 gene induction, decreased iNOS gene induction, inhibited 
      phosphorated-signal transducer and activator of transcription 1 (p-STAT1) but 
      enhanced p-STAT6 expression, much lower levels of proinflammatory TNF-alpha and IL-6, 
      and higher levels of anti-inflammatory IL-10 cytokine secretion. Signaling 
      pathway analysis revealed that peroxisome proliferator-activated receptor-gamma 
      (PPARgamma)/ STAT3 activation was upregulated in BMDMs with dexmedetomidine 
      pretreatment. Furthermore, PPARgamma knockdown by siRNA not only inhibited STAT3 
      activation but also abrogated the promotion effects of macrophage M2 activation 
      in BMDMs pretreated with dexmedetomidine. Finally, in vivo PPARgamma inhibition in 
      macrophages by siRNA significantly increased liver IR injury and intrahepatic 
      inflammation in mice from the Dex group, with no significant effect in the VEH 
      group. CONCLUSIONS: Our results indicate that dexmedetomidine preconditioning 
      inhibited intrahepatic proinflammatory innate immune activation by promoting 
      macrophage M2 activation in a PPARgamma/STAT3 dependent manner. Our results 
      demonstrate a novel innate immune regulatory mechanism by dexmedetomidine 
      preconditioning during liver IR injury.
CI  - Copyright (c) 2020. Published by Elsevier B.V.
FAU - Zhou, Haoming
AU  - Zhou H
AD  - Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of 
      Nanjing Medical University, Nanjing, China.
FAU - Sun, Jie
AU  - Sun J
AD  - Department of Anesthesiology, Zhongda Hospital, Southeast University. Nanjing, 
      China.
FAU - Zhong, Weizhe
AU  - Zhong W
AD  - Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of 
      Nanjing Medical University, Nanjing, China.
FAU - Pan, Xiongxiong
AU  - Pan X
AD  - Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, China.
FAU - Liu, Cunming
AU  - Liu C
AD  - Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, China.
FAU - Cheng, Feng
AU  - Cheng F
AD  - Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of 
      Nanjing Medical University, Nanjing, China.
FAU - Wang, Ping
AU  - Wang P
AD  - Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of 
      Nanjing Medical University, Nanjing, China. Electronic address: wuwpzhy@163.com.
FAU - Rao, Zhuqing
AU  - Rao Z
AD  - Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, China. Electronic address: zhuqingrao@njmu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20200304
PL  - Netherlands
TA  - Int Immunopharmacol
JT  - International immunopharmacology
JID - 100965259
SB  - IM
OTO - NOTNLM
OT  - Dexmedetomidine preconditioning
OT  - Inflammation
OT  - Liver ischemia and reperfusion injury
OT  - Macrophage
COIS- Declaration of Competing Interest The authors declare no conflicts of interest.
EDAT- 2020/03/08 06:00
MHDA- 2020/03/08 06:01
CRDT- 2020/03/08 06:00
PHST- 2019/10/23 00:00 [received]
PHST- 2020/02/05 00:00 [revised]
PHST- 2020/02/27 00:00 [accepted]
PHST- 2020/03/08 06:01 [medline]
PHST- 2020/03/08 06:00 [pubmed]
PHST- 2020/03/08 06:00 [entrez]
AID - S1567-5769(19)32429-4 [pii]
AID - 10.1016/j.intimp.2020.106363 [doi]
PST - aheadofprint
SO  - Int Immunopharmacol. 2020 Mar 4;82:106363. doi: 10.1016/j.intimp.2020.106363.