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.