Recombinant thrombomodulin protects against LPS-induced acute respiratory distress syndrome via preservation of pulmonary endothelial glycocalyx.
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
13
09
2019
revised:
15
04
2020
accepted:
28
05
2020
pubmed:
5
6
2020
medline:
22
6
2021
entrez:
5
6
2020
Statut:
ppublish
Résumé
Disruption of the endothelial glycocalyx is causally related to microvascular endothelial dysfunction, a characteristic of sepsis-induced acute respiratory distress syndrome (ARDS). Recombinant human thrombomodulin (rhTM) attenuates vascular endothelial injuries, but the underlying mechanism remains elusive. Here, we investigated the structural basis and molecular mechanisms of rhTM effects on vascular endothelial injury in a model of sepsis. LPS (20 mg·kg Survival rate of rhTM-treated mice was significantly higher than that of control mice 48 h after LPS injection. Serum concentrations of IL-6 and high-mobility group box 1 were lower in the rhTM-treated group than in the control. Injury to the endothelial glycocalyx in pulmonary capillaries was attenuated by rhTM treatment. Gene set enrichment analysis revealed up-regulation of gene sets corresponding to cell proliferation/differentiation and anti-inflammation, such as the TGF-β pathway, and negative regulation of IL-6, upon rhTM treatment. Gene expression of heparan sulfate 6-O-sulfotransferase 1 and endothelial cell-specific molecule 1 (components of the endothelial glycocalyx) was significantly preserved by rhTM treatment, and their protein expression levels were maintained in endothelial cells. Our findings show that rhTM treatment affected inflammation, cell proliferation/differentiation, and glycocalyx synthesis in serum and lung tissue, subsequently attenuating ARDS caused by endothelial injury.
Sections du résumé
BACKGROUND AND PURPOSE
Disruption of the endothelial glycocalyx is causally related to microvascular endothelial dysfunction, a characteristic of sepsis-induced acute respiratory distress syndrome (ARDS). Recombinant human thrombomodulin (rhTM) attenuates vascular endothelial injuries, but the underlying mechanism remains elusive. Here, we investigated the structural basis and molecular mechanisms of rhTM effects on vascular endothelial injury in a model of sepsis.
EXPERIMENTAL APPROACH
LPS (20 mg·kg
KEY RESULTS
Survival rate of rhTM-treated mice was significantly higher than that of control mice 48 h after LPS injection. Serum concentrations of IL-6 and high-mobility group box 1 were lower in the rhTM-treated group than in the control. Injury to the endothelial glycocalyx in pulmonary capillaries was attenuated by rhTM treatment. Gene set enrichment analysis revealed up-regulation of gene sets corresponding to cell proliferation/differentiation and anti-inflammation, such as the TGF-β pathway, and negative regulation of IL-6, upon rhTM treatment. Gene expression of heparan sulfate 6-O-sulfotransferase 1 and endothelial cell-specific molecule 1 (components of the endothelial glycocalyx) was significantly preserved by rhTM treatment, and their protein expression levels were maintained in endothelial cells.
CONCLUSION AND IMPLICATIONS
Our findings show that rhTM treatment affected inflammation, cell proliferation/differentiation, and glycocalyx synthesis in serum and lung tissue, subsequently attenuating ARDS caused by endothelial injury.
Identifiants
pubmed: 32497259
doi: 10.1111/bph.15153
pmc: PMC7429482
doi:
Substances chimiques
Lipopolysaccharides
0
Thrombomodulin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4021-4033Subventions
Organisme : Asahi Kasei Pharma Corporation
Organisme : Japan Society for the Promotion of Science
ID : 15K10973
Organisme : Japan Society for the Promotion of Science
ID : 16H05497
Organisme : Japan Society for the Promotion of Science
ID : 16K09509
Organisme : Japan Society for the Promotion of Science
ID : 16K20381
Organisme : Japan Society for the Promotion of Science
ID : 17K11569
Organisme : Japan Society for the Promotion of Science
ID : 18K08884
Organisme : Japan Society for the Promotion of Science
ID : 18K08914
Organisme : Japan Society for the Promotion of Science
ID : 18K16511
Organisme : Japan Society for the Promotion of Science
ID : 19H03756
Organisme : Japan Society for the Promotion of Science
ID : 19K09410
Organisme : Japan Society for the Promotion of Science
ID : 19K18347
Informations de copyright
© 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
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