Sphingolipids in Ventilator Induced Lung Injury: Role of Sphingosine-1-Phosphate Lyase.

Vidyani Suryadevara,Evgeny Berdyshev,Viswanathan Natarajan,Panfeng Fu,Anantha Harijith,Long Shuang Huang,Irina A Bronova,David Lenin Ebenezer

doi:10.3390/ijms19010114

Abstract

Mechanical ventilation (MV) performed in respiratory failure patients to maintain lung function leads to ventilator-induced lung injury (VILI). This study investigates the role of sphingolipids and sphingolipid metabolizing enzymes in VILI using a rodent model of VILI and alveolar epithelial cells subjected to cyclic stretch (CS). MV (0 PEEP (Positive End Expiratory Pressure), 30 mL/kg, 4 h) in mice enhanced sphingosine-1-phosphate lyase (S1PL) expression, and ceramide levels, and decreased S1P levels in lung tissue, thereby leading to lung inflammation, injury and apoptosis. Accumulation of S1P in cells is a balance between its synthesis catalyzed by sphingosine kinase (SphK) 1 and 2 and catabolism mediated by S1P phosphatases and S1PL. Thus, the role of S1PL and SphK1 in VILI was investigated using Sgpl1+/− and Sphk1−/− mice. Partial genetic deletion of Sgpl1 protected mice against VILI, whereas deletion of SphK1 accentuated VILI in mice. Alveolar epithelial MLE-12 cells subjected to pathophysiological 18% cyclic stretch (CS) exhibited increased S1PL protein expression and dysregulation of sphingoid bases levels as compared to physiological 5% CS. Pre-treatment of MLE-12 cells with S1PL inhibitor, 4-deoxypyridoxine, attenuated 18% CS-induced barrier dysfunction, minimized cell apoptosis and cytokine secretion. These results suggest that inhibition of S1PL that increases S1P levels may offer protection against VILI.

Highlights

Acute lung injury (ALI) is a cause of acute respiratory failure in patients experiencing sepsis, pneumonia, gastric aspiration, and trauma [1]
mechanical ventilation (MV) of mouse lungs resulted in a significant increase in ceramide (~1.5-fold) (Figure 1A) and a decrease in S1P (~2.5 fold) (Figure 1B) levels as compared to animals with spontaneous breathing; there was no change in sphingosine level (Figure 1C) between the two groups
We found that ceramide levels to be elevated in the lung after MV and in alveolar epithelial cells subjected to cyclic stretch (Figures 1 and 5)

Summary

Introduction

Acute lung injury (ALI) is a cause of acute respiratory failure in patients experiencing sepsis, pneumonia, gastric aspiration, and trauma [1]. Patients with ALI develop a protein-rich pulmonary edema resulting from exudation of fluid into the interstitial space of the lung. The pathobiological basis of these changes results in increased permeability of the vascular barrier, a hallmark of ALI. One pathophysiological consequence of pulmonary edema is accumulation of fluid in the lung interstitial spaces that results in impaired gas exchange [2], one of the reasons why assisted ventilation is required to support most patients. VILI is characterized by significant structural changes in the lungs, wherein there is a loss of alveolar permeability, influx of pro-inflammatory cytokines and alveolar epithelial apoptosis [4]. There is increased pulmonary pressure, reduced compliance and increased physiological dead space in the lungs

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Results

Conclusion