PMID- 33729030
OWN - NLM
STAT- MEDLINE
DCOM- 20210727
LR  - 20210727
IS  - 1522-1504 (Electronic)
IS  - 1040-0605 (Linking)
VI  - 320
IP  - 6
DP  - 2021 Jun 1
TI  - Geranylgeranyl diphosphate synthase deficiency hyperactivates macrophages and 
      aggravates lipopolysaccharide-induced acute lung injury.
PG  - L1011-L1024
LID - 10.1152/ajplung.00281.2020 [doi]
AB  - Macrophage activation is a key contributing factor for excessive inflammatory 
      responses of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). 
      Geranylgeranyl diphosphate synthase (GGPPS) plays a key role in the development 
      of inflammatory diseases. Our group previously showed that GGPPS in alveolar 
      epithelium have deleterious effects on acute lung injury induced by LPS or 
      mechanical ventilation. Herein, we examined the role of GGPPS in modulating 
      macrophage activation in ALI/ARDS. We found significant increased GGPPS 
      expression in alveolar macrophages in patients with ARDS compared with healthy 
      volunteers and in ALI mice induced by LPS. GGPPS-floxed control (GGPPS(fl/fl)) 
      and myeloid-selective knockout (GGPPS(fl/fl)LysMcre) mice were then generated. 
      Interestingly, using an LPS-induced ALI mouse model, we showed that 
      myeloid-specific GGPPS knockout significantly increased mortality, aggravated 
      lung injury, and increased the accumulation of inflammatory cells, total protein, 
      and inflammatory cytokines in BALF. In vitro, GGPPS deficiency upregulated the 
      production of LPS-induced IL-6, IL-1beta, and TNF-alpha in alveolar macrophages, bone 
      marrow-derived macrophages (BMDMs), and THP-1 cells. Mechanistically, GGPPS 
      knockout increased phosphorylation and nuclear translocation of NF-kappaB p65 induced 
      by LPS. In addition, GGPPS deficiency increased the level of GTP-Rac1, which was 
      responsible for NF-kappaB activation. In conclusion, decreased expression of GGPPS in 
      macrophages aggravates lung injury and inflammation in ARDS, at least partly by 
      regulating Rac1-dependent NF-kappaB signaling. GGPPS in macrophages may represent a 
      novel therapeutic target in ARDS.
FAU - Jin, Jiajia
AU  - Jin J
AD  - Department of Respiratory and Critical Care Medicine, Jinling Hospital, the First 
      School of Clinical Medicine, Southern Medical University (Guangzhou), Nanjing, 
      China.
AD  - Department of Respiratory Medicine, Nanjing First Hospital, Nanjing Medical 
      University, Nanjing, China.
FAU - Qian, Hong
AU  - Qian H
AD  - Department of Orthopaedic Surgery, Jinling Hospital, the First School of Clinical 
      Medicine, Southern Medical University, Nanjing, China.
FAU - Wan, Bing
AU  - Wan B
AD  - Department of Respiratory and Critical Care Medicine, The Affiliated Jiangning 
      Hospital of Nanjing Medical University, Nanjing, China.
FAU - Zhou, Li
AU  - Zhou L
AD  - Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical 
      School of Nanjing University, Nanjing, China.
FAU - Chen, Cen
AU  - Chen C
AD  - Department of Respiratory and Critical Care Medicine, Jinling Hospital, the First 
      School of Clinical Medicine, Southern Medical University (Guangzhou), Nanjing, 
      China.
FAU - Lv, Yanling
AU  - Lv Y
AD  - The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, 
      China.
FAU - Chen, Meizi
AU  - Chen M
AD  - Department of General Internal Medicine, the First People's Hospital of Chenzhou, 
      Chenzhou, China.
FAU - Zhu, Suhua
AU  - Zhu S
AD  - Department of Respiratory and Critical Care Medicine, Jinling Hospital, the First 
      School of Clinical Medicine, Southern Medical University (Guangzhou), Nanjing, 
      China.
FAU - Ye, Liang
AU  - Ye L
AD  - Department of Respiratory Medicine, Nanjing First Hospital, Nanjing Medical 
      University, Nanjing, China.
FAU - Wang, Xiaoxia
AU  - Wang X
AD  - Department of Intensive Care Unit, Inner Mongolia People's Hospital, Inner 
      Mongolia Autonomous Region, Hohhot, China.
FAU - Xu, Wujian
AU  - Xu W
AD  - Department of Respiratory and Critical Care Medicine, Jinling Hospital, the First 
      School of Clinical Medicine, Southern Medical University (Guangzhou), Nanjing, 
      China.
FAU - Lv, Tangfeng
AU  - Lv T
AD  - Department of Respiratory and Critical Care Medicine, Jinling Hospital, the First 
      School of Clinical Medicine, Southern Medical University (Guangzhou), Nanjing, 
      China.
FAU - Song, Yong
AU  - Song Y
AD  - Department of Respiratory and Critical Care Medicine, Jinling Hospital, the First 
      School of Clinical Medicine, Southern Medical University (Guangzhou), Nanjing, 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210317
PL  - United States
TA  - Am J Physiol Lung Cell Mol Physiol
JT  - American journal of physiology. Lung cellular and molecular physiology
JID - 100901229
RN  - 0 (Cytokines)
RN  - 0 (Lipopolysaccharides)
SB  - IM
MH  - Acute Lung Injury/chemically induced/*drug therapy/metabolism
MH  - Animals
MH  - Cytokines/metabolism
MH  - Disease Models, Animal
MH  - Gene Expression Regulation/drug effects
MH  - Inflammation/drug therapy/metabolism
MH  - Lipopolysaccharides/*pharmacology
MH  - Lung/drug effects/metabolism
MH  - Macrophage Activation/*drug effects
MH  - Macrophages/*drug effects/metabolism
MH  - Mice
OTO - NOTNLM
OT  - ARDS
OT  - GGPPS
OT  - NF-kappaB
OT  - Rac1
OT  - macrophage
EDAT- 2021/03/18 06:00
MHDA- 2021/07/28 06:00
CRDT- 2021/03/17 12:20
PHST- 2021/03/18 06:00 [pubmed]
PHST- 2021/07/28 06:00 [medline]
PHST- 2021/03/17 12:20 [entrez]
AID - 10.1152/ajplung.00281.2020 [doi]
PST - ppublish
SO  - Am J Physiol Lung Cell Mol Physiol. 2021 Jun 1;320(6):L1011-L1024. doi: 
      10.1152/ajplung.00281.2020. Epub 2021 Mar 17.