Role of endothelial microRNA 155 on capillary leakage in systemic inflammation

Autor: Matijs van Meurs, Valerie Etzrodt, Robert Geffers, Ankita Garg, Thorben Pape, Hermann Haller, Temitayo O Idowu, Antje Prasse, Janina Müller-Deile, Thomas Thum, Samir M. Parikh, Benjamin Seeliger, Heiko Schenk, Kristina Thamm, Klaus Stahl, Sascha David
Přispěvatelé: Groningen Kidney Center (GKC), Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., University of Zurich, David, Sascha
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Endothelium
Respiratory distress syndrome
610 Medicine & health
030204 cardiovascular system & hematology
Critical Care and Intensive Care Medicine
Systemic inflammation
Umbilical vein
03 medical and health sciences
Mice
0302 clinical medicine
Downregulation and upregulation
In vivo
Sepsis
Medicine
Animals
Humans
ddc:610
Tight junctions
Zebrafish
030304 developmental biology
0303 health sciences
Tight junction
business.industry
Research
lcsh:Medical emergencies. Critical care. Intensive care. First aid
Heterozygote advantage
lcsh:RC86-88.9
Systemic Inflammatory Response Syndrome
MicroRNAs
medicine.anatomical_structure
Knockout mouse
Cancer research
Endothelium
Vascular
10023 Institute of Intensive Care Medicine
medicine.symptom
2706 Critical Care and Intensive Care Medicine
business
Capillary Leak Syndrome
Zdroj: Critical Care
Critical care, 25(1):76. BMC
Critical care (London, England)
England
Critical Care, Vol 25, Iss 1, Pp 1-12 (2021)
ISSN: 1466-609X
1364-8535
Popis: Background Capillary leakage is a key contributor to the pathological host response to infections. The underlying mechanisms remain incompletely understood, and the role of microRNAs (MIR) has not been investigated in detail. We hypothesized that specific MIRs might be regulated directly in the endothelium thereby contributing to vascular leakage. Methods SmallRNA sequencing of endotoxemic murine pulmonary endothelial cells (ECs) was done to detect regulated vascular MIRs. In vivo models: transgenic zebrafish (flk1:mCherry/l-fabp:eGFP-DPB), knockout/wildtype mouse (B6.Cg-Mir155tm1.1Rsky/J); disease models: LPS 17.5 mg/kgBW and cecal ligation and puncture (CLP); in vitro models: stimulated human umbilical vein EC (HUVECs), transendothelial electrical resistance. Results Endothelial MIR155 was identified as a promising candidate in endotoxemic murine pulmonary ECs (25 × upregulation). Experimental overexpression in a transgenic zebrafish line and in HUVECs was sufficient to induce spontaneous vascular leakage. To the contrary, genetic MIR155 reduction protects against permeability both in vitro and in endotoxemia in vivo in MIR155 heterozygote knockout mice thereby improving survival by 40%. A tight junction protein, Claudin-1, was down-regulated both in endotoxemia and by experimental MIR155 overexpression. Translationally, MIR155 was detectable at high levels in bronchoalveolar fluid of patients with ARDS compared to healthy human subjects. Conclusions We found that MIR155 is upregulated in the endothelium in mouse and men as part of a systemic inflammatory response and might contribute to the pathophysiology of vascular leakage in a Claudin-1-dependent manner. Future studies have to clarify whether MIR155 could be a potential therapeutic target.
Databáze: OpenAIRE
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