PMID- 28671983
OWN - NLM
STAT- MEDLINE
DCOM- 20171002
LR  - 20210831
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 7
DP  - 2017
TI  - Isoflurane promotes phagocytosis of apoptotic neutrophils through AMPK-mediated 
      ADAM17/Mer signaling.
PG  - e0180213
LID - 10.1371/journal.pone.0180213 [doi]
LID - e0180213
AB  - A patient's recovery from lung inflammatory injury or development of multi-system 
      organ failure is determined by the host's ability to resolve inflammation and 
      repair tissue damage, both of which require the clearance of apoptotic 
      neutrophils by macrophages (efferocytosis). Here, we investigated the effects of 
      isoflurane on macrophage efferocytosis and resolution of lung inflammatory 
      injury. Treatment of murine bone marrow-derived macrophages (BMDMs) or alveolar 
      macrophages with isoflurane dramatically enhanced phagocytosis of apoptotic 
      neutrophils. Isoflurane significantly increased the surface expression of the 
      receptor tyrosine kinase Mer in macrophages, but markedly decreased the levels of 
      a soluble form of Mer protein in the medium. Isoflurane treatment also caused a 
      decrease in a disintegrin and metalloproteinase 17 (ADAM17) on the cell surface 
      and a concomitant increase in its cytoplasmic fraction. These responses induced 
      by isoflurane were completely reversed by a pharmacological inhibitor or genetic 
      deletion of AMP-activated protein kinase (AMPK). In a mouse model of 
      lipopolysaccharide-induced lung injury, isoflurane accelerated the recovery of 
      lung inflammation and injury that was coupled with an increase in the number of 
      alveolar macrophages containing apoptotic bodies. In alveolar macrophage-depleted 
      mice, administration of isoflurane-pretreated BMDMs facilitated resolution of 
      lung inflammation following lipopolysaccharide challenge. Thus, isoflurane 
      promoted resolution of lipopolysaccharide-induced lung inflammatory injury via 
      enhancement of macrophage efferocytosis. Increased macrophage efferocytosis 
      following isoflurane treatment correlates with upregulation of Mer surface 
      expression through AMPK-mediated blockade of ADAM17 trafficking to the cell 
      membrane.
FAU - Du, Xueke
AU  - Du X
AD  - Department of Anesthesiology, University of Illinois College of Medicine, 
      Chicago, Illinois, United States of America.
AD  - Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China.
FAU - Jiang, Chunling
AU  - Jiang C
AD  - Department of Anesthesiology, University of Illinois College of Medicine, 
      Chicago, Illinois, United States of America.
FAU - Lv, Yang
AU  - Lv Y
AD  - Department of Anesthesiology, University of Illinois College of Medicine, 
      Chicago, Illinois, United States of America.
FAU - Dull, Randal O
AU  - Dull RO
AD  - Department of Anesthesiology, University of Illinois College of Medicine, 
      Chicago, Illinois, United States of America.
FAU - Zhao, You-Yang
AU  - Zhao YY
AD  - Department of Pharmacology, University of Illinois College of Medicine, Chicago, 
      Illinois, United States of America.
AD  - Center for Lung and Vascular Biology, University of Illinois College of Medicine, 
      Chicago, Illinois, United States of America.
FAU - Schwartz, David E
AU  - Schwartz DE
AD  - Department of Anesthesiology, University of Illinois College of Medicine, 
      Chicago, Illinois, United States of America.
FAU - Hu, Guochang
AU  - Hu G
AUID- ORCID: 0000-0002-7054-7867
AD  - Department of Anesthesiology, University of Illinois College of Medicine, 
      Chicago, Illinois, United States of America.
AD  - Department of Pharmacology, University of Illinois College of Medicine, Chicago, 
      Illinois, United States of America.
AD  - The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
LA  - eng
GR  - P01 HL077806/HL/NHLBI NIH HHS/United States
GR  - R01 HL104092/HL/NHLBI NIH HHS/United States
GR  - R01 HL125350/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20170703
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antigens, Differentiation, B-Lymphocyte)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (mouse erythrocyte receptor)
RN  - CYS9AKD70P (Isoflurane)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 3.4.24.86 (ADAM17 Protein)
SB  - IM
MH  - ADAM17 Protein/*metabolism
MH  - AMP-Activated Protein Kinases/genetics/*metabolism
MH  - Acute Lung Injury/chemically induced
MH  - Animals
MH  - Antigens, Differentiation, B-Lymphocyte/*metabolism
MH  - *Apoptosis
MH  - Cells, Cultured
MH  - Gene Knockdown Techniques
MH  - Isoflurane/*pharmacology
MH  - Lipopolysaccharides/pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neutrophils/*drug effects/immunology
MH  - Phagocytosis/*drug effects
MH  - Receptors, Immunologic/*metabolism
MH  - *Signal Transduction
PMC - PMC5495389
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2017/07/04 06:00
MHDA- 2017/10/03 06:00
PMCR- 2017/07/03
CRDT- 2017/07/04 06:00
PHST- 2017/04/10 00:00 [received]
PHST- 2017/06/12 00:00 [accepted]
PHST- 2017/07/04 06:00 [entrez]
PHST- 2017/07/04 06:00 [pubmed]
PHST- 2017/10/03 06:00 [medline]
PHST- 2017/07/03 00:00 [pmc-release]
AID - PONE-D-17-13934 [pii]
AID - 10.1371/journal.pone.0180213 [doi]
PST - epublish
SO  - PLoS One. 2017 Jul 3;12(7):e0180213. doi: 10.1371/journal.pone.0180213. 
      eCollection 2017.