PMID- 34066510
OWN - NLM
STAT- MEDLINE
DCOM- 20210617
LR  - 20240226
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 9
DP  - 2021 May 6
TI  - Effects of Thrombomodulin in Reducing Lethality and Suppressing Neutrophil 
      Extracellular Trap Formation in the Lungs and Liver in a 
      Lipopolysaccharide-Induced Murine Septic Shock Model.
LID - 10.3390/ijms22094933 [doi]
LID - 4933
AB  - Neutrophil extracellular trap (NET) formation, an innate immune system response, 
      is associated with thrombogenesis and vascular endothelial injury. Circulatory 
      disorders due to microvascular thrombogenesis are one of the principal causes of 
      organ damage. NET formation in organs contributes to the exacerbation of sepsis, 
      which is defined as a life-threatening organ dysfunction caused by a dysregulated 
      host response to infection. We have previously reported that recombinant human 
      soluble thrombomodulin (rTM) reduces lipopolysaccharide (LPS)-induced NET 
      formation in vitro. Here, we aimed to show that thrombomodulin (TM)-mediated 
      suppression of NET formation protects against organ damage in sepsis. Mice were 
      injected intraperitoneally (i.p.) with 10 mg/kg LPS. rTM (6 mg/kg/day) or saline 
      was administered i.p. 1 h after LPS injection. In the LPS-induced murine septic 
      shock model, extracellular histones, which are components of NETs, were observed 
      in the liver and lungs. In addition, the serum cytokine (interleukin-1beta (IL-1beta), 
      interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), macrophage chemotactic 
      protein-1 (MCP-1), and interleukin-10 (IL-10)) levels were increased. The 
      administration of rTM in this model prevented NET formation in the organs and 
      suppressed the increase in the levels of all cytokines except IL-1beta. Furthermore, 
      the survival rate improved. We provide a novel role of TM in treating 
      inflammation and NETs in organs during sepsis.
FAU - Kato, Yu
AU  - Kato Y
AD  - Department of Anesthesiology and Critical Care Medicine, Fujita Health University 
      School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan.
FAU - Nishida, Osamu
AU  - Nishida O
AD  - Department of Anesthesiology and Critical Care Medicine, Fujita Health University 
      School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan.
FAU - Kuriyama, Naohide
AU  - Kuriyama N
AD  - Department of Anesthesiology and Critical Care Medicine, Fujita Health University 
      School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan.
FAU - Nakamura, Tomoyuki
AU  - Nakamura T
AD  - Department of Anesthesiology and Critical Care Medicine, Fujita Health University 
      School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan.
FAU - Kawaji, Takahiro
AU  - Kawaji T
AD  - Department of Anesthesiology and Critical Care Medicine, Fujita Health University 
      School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan.
FAU - Onouchi, Takanori
AU  - Onouchi T
AD  - Center for Joint Research Facilities Support, Research Promotion and Support 
      Headquarters, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, 
      Toyoake 470-1192, Japan.
FAU - Hasegawa, Daisuke
AU  - Hasegawa D
AUID- ORCID: 0000-0001-7647-522X
AD  - Department of Anesthesiology and Critical Care Medicine, Fujita Health University 
      School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan.
FAU - Shimomura, Yasuyo
AU  - Shimomura Y
AUID- ORCID: 0000-0002-4125-0060
AD  - Department of Anesthesiology and Critical Care Medicine, Fujita Health University 
      School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan.
LA  - eng
GR  - 17K17072, 17K11064/Japan Society for the Promotion of Science/
PT  - Journal Article
DEP - 20210506
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Cytokines)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Thrombomodulin)
SB  - IM
MH  - Animals
MH  - Cytokines/blood
MH  - Disease Models, Animal
MH  - Extracellular Traps/drug effects/*metabolism
MH  - Female
MH  - Humans
MH  - Lipopolysaccharides
MH  - Liver/*pathology/ultrastructure
MH  - Lung/*pathology
MH  - Mice, Inbred C57BL
MH  - Recombinant Proteins/administration & dosage/pharmacology/therapeutic use
MH  - Shock, Septic/blood/chemically induced/*drug therapy
MH  - Survival Analysis
MH  - Thrombomodulin/*therapeutic use
MH  - Mice
PMC - PMC8124404
OTO - NOTNLM
OT  - lipopolysaccharide (LPS)
OT  - neutrophil extracellular traps (NETs)
OT  - organ dysfunction
OT  - sepsis
OT  - thrombomodulin
COIS- Asahi Kasei Pharma Corporation provided recombinant human-soluble thrombomodulin 
      (ART-123). The investigation was investigator-initiated, and the provider was not 
      involved in the study design or conduct, and had no role in manuscript 
      preparation. The authors declare no conflict of interest.
EDAT- 2021/06/03 06:00
MHDA- 2021/06/22 06:00
PMCR- 2021/05/06
CRDT- 2021/06/02 01:16
PHST- 2021/03/04 00:00 [received]
PHST- 2021/04/30 00:00 [revised]
PHST- 2021/05/03 00:00 [accepted]
PHST- 2021/06/02 01:16 [entrez]
PHST- 2021/06/03 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2021/05/06 00:00 [pmc-release]
AID - ijms22094933 [pii]
AID - ijms-22-04933 [pii]
AID - 10.3390/ijms22094933 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 May 6;22(9):4933. doi: 10.3390/ijms22094933.