Upregulation of sphingosine kinase 1 contributes to ventilator-associated lung injury in a two-hit model.
Int J Mol Med
; 44(6): 2077-2090, 2019 Dec.
Article
em En
| MEDLINE
| ID: mdl-31638192
ABSTRACT
Ventilatorassociated lung injury (VALI) remains a significant medical problem in intensive care units. The present study aimed to investigate the role of sphingosine kinase 1 (SPHK1) in VALI using a twohit model and explore the potential underlying molecular mechanism. Mice were divided into five groups i) Nonventilated group; ii) nonventilated + lipopolysaccharide (LPS) group; iii) ventilated group; iv) ventilated + LPS group; and v) ventilated + LPS + SPHK1 inhibitor group. Mice were administered LPS (1 mg/kg) via an intraperitoneal injection. After 12 h, the mice were anesthetized and connected to a ventilator (10 ml/kg at 150 breaths/min) for 4 h. SPHK1 inhibitor (50 mg/kg) was injected intraperitoneally 1 h prior to ventilation. Mouse lung vascular endothelial cells were treated with LPS and SPHK1 inhibitor, and then subjected to cyclic stretch for 4 h. The present results suggested that the expression of SPHK1 and sphingosine 1 phosphate was upregulated in the twohit model of VALI; SPHK1 inhibitor could attenuate VALI in the twohit model as observed by hematoxylin and eosin staining, and affected the cell count and the protein content levels in the bronchoalveolar lavage fluid. In addition, treatment with SPHK1 inhibitor reduced the wettodry ratio of the lungs and suppressed Evans blue dye leakage into the lung tissue. Furthermore, SPHK1 inhibitor exhibited protective effects on the twohit model of VALI by inhibiting the Ras homolog family member amediated phosphorylation of myosin phosphatase target subunit 1 (MYPT1) and endothelial hyperpermeability. Additionally, mice were divided into five additional groups i) Nonventilated group; ii) nonventilated + LPS group; iii) ventilated group; iv) ventilated + LPS group; and v) ventilated + LPS + Rhoassociated coiledcoil forming protein kinase (ROCK)1 inhibitor group. ROCK1 inhibitor (10 mg/kg) was injected intraperitoneally 1 h prior to ventilation. The present results suggested that ROCK1 inhibitor could attenuate mechanical stretchinduced lung endothelial injury and the phosphorylation of MYPT1 in vivo and in vitro. Collectively, the present findings indicated that upregulation of SPHK1 may contribute to VALI in a twohit model.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfotransferases (Aceptor do Grupo Álcool)
/
Fosfatase de Miosina-de-Cadeia-Leve
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Quinases Associadas a rho
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Lesão Pulmonar Induzida por Ventilação Mecânica
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Int J Mol Med
Assunto da revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Ano de publicação:
2019
Tipo de documento:
Article