Role of the Nucleotide-Binding Domain-Like Receptor Protein 3 Inflammasome in the Endothelial Dysfunction of Early Sepsis

Endothelial dysfunction is responsible for multiple organ failure and the high mortality rate of sepsis. Nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome plays an essential role in the progression of sepsis. However, the role of NLRP3 inflammasome in the endothelial dysfunction...

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Vydáno v:Inflammation Ročník 43; číslo 4; s. 1561 - 1571
Hlavní autoři: Luo, Minghao, Meng, Jiayu, Yan, Jianghong, Shang, Feifei, Zhang, Ting, Lv, Dingyi, Li, Chang, Yang, Xiyang, Luo, Suxin
Médium: Journal Article
Jazyk:angličtina
Vydáno: New York Springer US 01.08.2020
Springer Nature B.V
Témata:
Aorta
Biomedical and Life Sciences
Biomedicine
Cecum
Coronary vessels
Endothelial cells
Endothelium
IL-1β
Immunology
Inflammasomes
Interleukin 1
Interleukin 1 receptor antagonist
Interleukin 1 receptors
Internal Medicine
Lipopolysaccharides
Mortality
MyD88 protein
Nitric oxide
Nitric-oxide synthase
Original Article
Pathology
Pharmacology/Toxicology
Rheumatology
Sepsis
Therapeutic applications
TLR4 protein
Toll-like receptors
Umbilical vein
Vasodilation
NLRP3
eNOS
endothelial dysfunction
sepsis
ISSN:0360-3997, 1573-2576, 1573-2576
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Shrnutí:Endothelial dysfunction is responsible for multiple organ failure and the high mortality rate of sepsis. Nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome plays an essential role in the progression of sepsis. However, the role of NLRP3 inflammasome in the endothelial dysfunction of sepsis has not been fully elucidated. In this study, septic mice were induced by cecal ligation and puncture (CLP) operation, and human umbilical vein endothelial cells ( HUVECs) were treated with lipopolysaccharide (LPS). The 24-h survival rate after CLP was observed. Vasodilation function of the aorta was detected by vascular reactivity experiments. Expression of p-eNOS, eNOS, TLR4, MYD88, p-p65, p65, p-ikbα, ikbα, iNOS, NLRP3, and IL-1β in the aorta and HUVECs were determined by Western blot. Our results suggest that the p-eNOS expression was downregulated, the endothelium-dependent relaxation function was impaired, and TLR4, MYD88, p-p65, p-ikbα, iNOS, NLRP3, and IL-1β expression increased after CLP. The onset of death was 12 h after CLP, and the mortality rate was nearly 50% at 24 h after operation. The decline of p-eNOS, endothelium-dependent vasodilation function, and survival rate significantly improved with NLRP3-specific inhibitor MCC950 intervention or NLRP3 knockout in CLP mice. The decrease of p-eNOS in HUVECs induced by LPS was alleviated when pretreated with MCC950 or interleukin-1 receptor antagonist (IL-1Ra). In summary, our results indicate that activation of the NLRP3 inflammasome contributes to the development of endothelial dysfunction of early sepsis in mice, suggesting its potential role as a therapeutic target for the treatment of sepsis.
Bibliografie:ObjectType-Article-1
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ISSN:0360-3997
1573-2576
1573-2576
DOI:10.1007/s10753-020-01232-x