Abstract
Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor and inhibits cholesterol synthesis. Recently, atorvastatin also showed anti-inflammatory effect in acute lung injury, ameliorating pulmonary gas-blood exchanging function. Sphingosine kinase 1 plays a central role in endothelial (EC) cytoskeleton rearrangement and EC barrier integrity regulation. In this study, the role of sphingosine kinase 1 in atorvastatin anti-inflammatory effect against acute lung injury was investigated. Both wild-type (WT) and SphK1−/− mice were challenged with high tidal volume ventilation (40 ml/kg body weight, 65 breathing/min, 4 hours). The acute lung injury was evaluated and the mechanisms were explored. In WT mice, atorvastatin treatment significantly decreased acute lung injury responding to high tidal volume ventilation (HT), including protein, cellular infiltration, and cytokine releasing; comparing to WT mice, SphK1−/− mice showed significantly worsen pulmonary injuries on HT model. Moreover, the atorvastatin-mediated anti-inflammatory effect was diminished in SphK1−/− mice. To further confirm the role of SphK1 in VILI, we then compared the inflammatory response of endothelial cells that were isolated from WT and SphK1−/− mice to cyclic stretching. Similarly, atorvastatin significantly decreased cytokine generation from WT EC responding to cyclic stretching. Atorvastatin also significantly preserved endothelial junction integrity in WT EC against thrombin challenge. However, the inhibitory effect of atorvastatin on cytokine generation induced by cyclic stretching was abolished on SphK1−/− mice EC. The endothelial junction integrity effects of atorvastatin also diminished on SphK1−/− mouse EC. Signal analysis indicated that atorvastatin inhibited JNK activation induced by cyclic stretch. SphK1 knockout also blocked atorvastatin-mediated VE-cadherin junction enhancement. In summary, by inhibition of MAPK activity and maintenance of EC junction homeostasis, SphK1 plays a critical role in atorvastatin-mediated anti-inflammatory effects in both cellular and in vivo model. This study also offers an insight into mechanical stress-mediated acute lung injury and potential therapy in the future.
Highlights
Atorvastatin is a member of statin family inhibiting of 3hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoA reductase) and modulates cholesterol synthesis [1]
Endothelial junction studies indicated that SphK1 plays a central role in endothelial junction reorganization and integrity maintenance, which partially contributes to the anti-inflammatory effect of atorvastatin (Figure 8)
The involvements of endothelium in Ventilation-induced lung injury (VILI) include (1) increased lung vascular permeability due to loss of endothelial cell barrier integrity, (2) mechanical stress-induced inflammatory cytokine release and cell infiltration, and (3) genetic and epigenetic regulation of critical target genes such as junction protein and signal proteins that are involved in VILI response [17]
Summary
Atorvastatin is a member of statin family inhibiting of 3hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoA reductase) and modulates cholesterol synthesis [1]. In addition to inhibiting cholesterol synthesis, statins have multiple effects on clinical purposes, such as meliorating the patient’s quality of life [2, 3] Among these properties of statin, the anti-inflammatory effects and enhancement of pulmonary function have been widely investigated [4, 5]. We explored the mechanisms and importance of atorvastatin in high tidal volume ventilation-mediated acute lung injury using a sphingosine kinase 1 knockout mouse model. By regulating the SphK1MAPK signal pathway, atorvastatin meliorated high tidal volume ventilation-mediated acute lung injury. Atorvastatin regulates endothelial junction integrity by rearrangement of cytoskeleton system These findings may offer a new view and potential therapy for the high tidal volume ventilation-mediated acute lung injury
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