Sphingosine kinase-1 and sphingosine-1-phosphate promote the development of acute lung injury in pneumoccocal pneumonia
2012
Pneumonia may evoke acute lung injury. Basal plasma levels of sphingosine-1-phosphate (S1P) contribute to vascular integrity. Pulmonary S1P, mainly synthesized by sphingosine kinase-1 (SphK1), regulates inflammatory mechanisms. We examined SphK1 and S1P in pneumonia.
Serum and post mortem lungs of pneumonia patients were examined. Wildtype- (WT), SphK1-/-- and S1P-treated mice were infected with S. pneumoniae ( S.pn. ). Murine isolated perfused and ventilated lungs and human endothelial cell (HUVEC) monolayers were exposed to S1P and pneumolysin (PLY). Human lung tissue and human peripheral blood mononuclear cells (PBMCs) were infected with S.pn. ex vivo.
S1P was reduced in serum of patients and mice with pneumonia. Pulmonary S1P levels and mRNA expression of SphK1 and S1P receptor 2 (S1PR2) were increased in S.pn. –infected WT mice. Lung permeability was decreased in SphK1-/--mice and increased in S1P-treated mice as compared to untreated WT mice in pneumonia. S1P was reduced in ex vivo S.pn. -infected human lung tissue. In lungs of pneumonia patients, macrophages carried high amounts of SphK1. S.pn. -infected PBMCs showed increased S1P levels and SphK1 expression. S1P (1µM) reduced thrombin-induced but not PLY-induced HUVEC permeability. More S1P (100µM) evoked HUVEC disruption. In isolated lungs, PLY-induced permeability was dose-dependently and synergistically increased by S1P (0.1-1µM). The S1P-induced increase of permeability was abolished by inhibition of S1PR2 or its downstream effector Rho-kinase.
The current data suggest that targeting the SphK1–S1P–S1PR2 axis may provide a therapeutic perspective for prevention of acute lung injury in pneumococcal pneumonia.
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