Toll-like receptors 2 and 7 mediate coagulation activation and coagulopathy in murine sepsis.
Adaptor Proteins, Vesicular Transport
/ deficiency
Animals
Blood Coagulation
Blood Coagulation Disorders
/ blood
Cells, Cultured
Cytokines
/ blood
Disease Models, Animal
Macrophages
/ metabolism
Male
Mice, Inbred C57BL
Mice, Knockout
Myeloid Differentiation Factor 88
/ deficiency
Sepsis
/ blood
Signal Transduction
Thrombocytopenia
/ blood
Toll-Like Receptor 2
/ deficiency
Toll-Like Receptor 3
/ deficiency
ROTEM
Toll-like receptor
coagulopathy
microRNA
sepsis
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
01
03
2019
accepted:
10
06
2019
pubmed:
19
6
2019
medline:
25
8
2020
entrez:
19
6
2019
Statut:
ppublish
Résumé
Sepsis is a life-threatening condition often manifested as marked inflammation and severe coagulopathy. Toll-like receptors (TLRs) play a pivotal role in inflammation, organ dysfunction and mortality in animal sepsis. To investigate the role of TLR signaling in mediating sepsis-induced coagulopathy (SIC) in a mouse model. Polymicrobial sepsis was created by cecal ligation and puncture (CLP) or fecal slurry peritoneal injection. To quantify global clotting function, two viscoelastic assays were performed with rotational thromboelastometry, and the results were presented as maximum clot firmness (MCF): (a) EXTEM to test tissue factor (TF)-initiated clot formation; and (b) FIBTEM to test EXTEM in the presence of a platelet inhibitor, cytochalasin D. Plasma coagulation factors were quantified with ELISA. TF gene expression and protein expression were determined with real-time quantitative reverse transcription PCR and flow cytometry, respectively. Between 4 and 24 hours after CLP surgery, wild-type mice showed significant MCF reduction in both EXTEM and FIBTEM tests. This was accompanied by marked thrombocytopenia and a significant increase in the levels of plasminogen activator inhibitor-1, plasma TF, and D-dimer. In comparison, TLR2 Murine sepsis leads to an increased procoagulant response, thrombocytopenia, and global coagulopathy. TLR2 and TLR7 play an important role in procoagulant production and in SIC.
Sections du résumé
BACKGROUND
Sepsis is a life-threatening condition often manifested as marked inflammation and severe coagulopathy. Toll-like receptors (TLRs) play a pivotal role in inflammation, organ dysfunction and mortality in animal sepsis.
OBJECTIVES
To investigate the role of TLR signaling in mediating sepsis-induced coagulopathy (SIC) in a mouse model.
METHODS
Polymicrobial sepsis was created by cecal ligation and puncture (CLP) or fecal slurry peritoneal injection. To quantify global clotting function, two viscoelastic assays were performed with rotational thromboelastometry, and the results were presented as maximum clot firmness (MCF): (a) EXTEM to test tissue factor (TF)-initiated clot formation; and (b) FIBTEM to test EXTEM in the presence of a platelet inhibitor, cytochalasin D. Plasma coagulation factors were quantified with ELISA. TF gene expression and protein expression were determined with real-time quantitative reverse transcription PCR and flow cytometry, respectively.
RESULTS
Between 4 and 24 hours after CLP surgery, wild-type mice showed significant MCF reduction in both EXTEM and FIBTEM tests. This was accompanied by marked thrombocytopenia and a significant increase in the levels of plasminogen activator inhibitor-1, plasma TF, and D-dimer. In comparison, TLR2
CONCLUSIONS
Murine sepsis leads to an increased procoagulant response, thrombocytopenia, and global coagulopathy. TLR2 and TLR7 play an important role in procoagulant production and in SIC.
Identifiants
pubmed: 31211901
doi: 10.1111/jth.14543
pmc: PMC7197442
mid: NIHMS1036696
pii: S1538-7836(22)03348-7
doi:
Substances chimiques
Adaptor Proteins, Vesicular Transport
0
Cytokines
0
Myd88 protein, mouse
0
Myeloid Differentiation Factor 88
0
TICAM-1 protein, mouse
0
TLR3 protein, mouse
0
Tlr2 protein, mouse
0
Toll-Like Receptor 2
0
Toll-Like Receptor 3
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1683-1693Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM097259
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM117233
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM122908
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM124775
Pays : United States
Informations de copyright
© 2019 International Society on Thrombosis and Haemostasis.
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