Downregulation of R-Spondin1 Contributes to Mechanical Stretch-Induced Lung Injury.
Crit Care Med
; 47(7): e587-e596, 2019 07.
Article
in En
| MEDLINE
| ID: mdl-31205087
ABSTRACT
OBJECTIVES:
The R-spondin family attenuates tissue damage via tightening endothelium and preventing vascular leakage. This study aims to investigate whether R-spondins protect against mechanical stretch-induced endothelial dysfunction and lung injury and to reveal the underlying mechanisms.DESIGN:
Randomized controlled study.SETTING:
University research laboratory.SUBJECTS:
Patients scheduled to undergo surgery with mechanical ventilation support. Adult male Institute of Cancer Research mice. Primary cultured mouse lung vascular endothelial cells.INTERVENTIONS:
Patients underwent a surgical procedure with mechanical ventilation support of 3 hours or more. Mice were subjected to mechanical ventilation (6 or 30 mL/kg) for 0.5-4 hours. Another group of mice were intraperitoneally injected with 1 mg/kg lipopolysaccharide, and 12 hours later subjected to mechanical ventilation (10 mL/kg) for 4 hours. Mouse lung vascular endothelial cells were subjected to cyclic stretch for 4 hours. MEASUREMENTS AND MAINRESULTS:
R-spondin1 were downregulated in both surgical patients and experimental animals exposed to mechanical ventilation. Intratracheal instillation of R-spondin1 attenuated, whereas knockdown of pulmonary R-spondin1 exacerbated ventilator-induced lung injury and mechanical stretch-induced lung vascular endothelial cell apoptosis. The antiapoptotic effect of R-spondin1 was mediated through the leucine-rich repeat containing G-protein coupled receptor 5 in cyclic stretched mouse lung vascular endothelial cells. We identified apoptosis-stimulating protein of p53 2 as the intracellular signaling protein interacted with leucine-rich repeat containing G-protein coupled receptor 5. R-spondin1 treatment decreased the interaction of apoptosis-stimulating protein of p53 2 with p53 while increased the binding of apoptosis-stimulating protein of p53 2 to leucine-rich repeat containing G-protein coupled receptor 5, therefore resulting in inactivation of p53-mediated proapoptotic pathway in cyclic stretched mouse lung vascular endothelial cells.CONCLUSIONS:
Mechanical ventilation leads to down-regulation of R-spondin1. R-spondin1 may enhance the interaction of leucine-rich repeat containing G-protein coupled receptor 5 and apoptosis-stimulating protein of p53 2, thus inactivating p53-mediated proapoptotic pathway in cyclic stretched mouse lung vascular endothelial cells. R-spondin1 may have clinical benefit in alleviating mechanical ventilator-induced lung injury.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Down-Regulation
/
Thrombospondins
/
Ventilator-Induced Lung Injury
/
Lung
Limits:
Animals
Language:
En
Journal:
Crit Care Med
Year:
2019
Document type:
Article
Affiliation country:
China