Upregulation of sphingosine kinase�1 contributes to�ventilator-associated lung injury in a two-hit model

Abstract

Ventilator-associated 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 two-hit model and explore the potential underlying molecular mechanism. Mice were divided into five groups: i) Non-ventilated group; ii) non-ventilated + 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 two-hit model of VALI; SPHK1 inhibitor could attenuate VALI in the two-hit 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 wet-to-dry ratio of the lungs and suppressed Evans blue dye leakage into the lung tissue. Furthermore, SPHK1 inhibitor exhibited protective effects on the two-hit model of VALI by inhibiting the Ras homolog family member a-mediated phosphorylation of myosin phosphatase target subunit 1 (MYPT-1) and endothelial hyperpermeability. Additionally, mice were divided into five additional groups: i) Non-ventilated group; ii) non-ventilated + LPS group; iii) ventilated group; iv) ventilated + LPS group; and v) ventilated + LPS + Rho-associated coiled-coil 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 stretch-induced lung endothelial injury and the phosphorylation of MYPT-1 in vivo and in vitro. Collectively, the present findings indicated that upregulation of SPHK1 may contribute to VALI in a two-hit model.

Lysophospholipids in Lung Inflammatory Diseases

“…S1P levels in lung tissues and BALF, not in plasma, were upregulated in intratracheal (IT) LPS-induced acute lung injury [93]. Plasma S1P was increased in a two-hit model induced by intraperitoneal (IP) LPS combined with ventilation [94]. A recent study found that Pseudomonas aeruginosa challenge increases S1P levels in lungs and BALF [95].…”

“…In addition to its anti-acute lung injury property, SphK1 has been reported to contribute to the pathogenesis of lung injury. IP administration of SphK1 inhibitor exhibited protective effects on the two-hit (ventilation + IP LPS)-induced acute lung injury [94]. Gutbier B et al reported that SphK1-deficient mice had reduced lung hyperpermeability in a P. aeruginosa-induced murine model of acute lung injury [101]; however, another controversial study demonstrated that SphK1 knockout had no effects in P. aeruginosa-induced acute lung injury [95].…”

Untitled

“…Given the increased rate of thrombosis in COVID-19, the status of TFPI needs to be investigated with VPA-treatment. The VPA-induced downregulation of SPHK1 appears to help COVID-19 treatment as followed: SPHK1 is known to contribute to ventilator-associated lung injury [46]; elevated SPHK1 enhances influenza virus infection [47]; SPHK1 also serves as a pro-viral factor by regulating viral RNA synthesis and nuclear export of viral ribonucleoprotein complex upon influenza virus infection [48]. VPA-induced downregulation of SPHK appears to be helpful in the treatment of COVID-19 patients.…”

Mechanisms of Mechanical Force Induced Pulmonary Vascular Endothelial Hyperpermeability

“…The activation of RhoA induces the phosphorylation of MLC and contraction of ECs, resulting in gap formation and increased endothelial permeability ( Liu et al, 2013 ). Rock inhibitor could attenuate CS-induced lung endothelial hyperpermeability and the phosphorylation of myosin phosphatase target subunit 1 in vivo and in vitro ( Wang et al, 2019 ). 1-palmitoyl-2-arachidonoyl-snglycero-3-phosphatidyl choline showed a protective role of stretch-induced barrier-disruptive via triggering Rac activation ( Birukova et al, 2011 ).…”