TY  - JOUR
A1  - Gutbier, Birgitt
A1  - Schönrock, Stefanie M.
A1  - Ehrler, Carolin
A1  - Haberberger, Rainer
A1  - Dietert, Kristina
A1  - Gruber, Achim D.
A1  - Kummer, Wolfgang
A1  - Michalick, Laura
A1  - Kuebler, Wolfgang M.
A1  - Hocke, Andreas C.
A1  - Szymanski, Kolja
A1  - Letsiou, Eleftheria
A1  - Lüth, Anja
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Mitchell, Timothy J.
A1  - Bertrams, Wilhelm
A1  - Schmeck, Bernd
A1  - Treue, Denise
A1  - Klauschen, Frederick
A1  - Bauer, Torsten T.
A1  - Tönnies, Mario
A1  - Weissmann, Norbert
A1  - Hippenstiel, Stefan
A1  - Suttorp, Norbert
A1  - Witzenrath, Martin
T1  - Sphingosine Kinase 1 Regulates Inflammation and Contributes to Acute Lung Injury in Pneumococcal Pneumonia via the Sphingosine-1-Phosphate Receptor 2
JF  - Critical care medicine
N2  - Objectives: Severe pneumonia may evoke acute lung injury, and sphingosine-1-phosphate is involved in the regulation of vascular permeability and immune responses. However, the role of sphingosine-1-phosphate and the sphingosine-1-phosphate producing sphingosine kinase 1 in pneumonia remains elusive. We examined the role of the sphingosine-1-phosphate system in regulating pulmonary vascular barrier function in bacterial pneumonia. Design: Controlled, in vitro, ex vivo, and in vivo laboratory study. Subjects: Female wild-type and SphK1-deficient mice, 8-10 weeks old. Human postmortem lung tissue, human blood-derived macrophages, and pulmonary microvascular endothelial cells. Interventions: Wild-type and SphK1-deficient mice were infected with Streptococcus pneumoniae. Pulmonary sphingosine-1-phosphate levels, messenger RNA expression, and permeability as well as lung morphology were analyzed. Human blood-derived macrophages and human pulmonary microvascular endothelial cells were infected with S. pneumoniae. Transcellular electrical resistance of human pulmonary microvascular endothelial cell monolayers was examined. Further, permeability of murine isolated perfused lungs was determined following exposition to sphingosine-1-phosphate and pneumolysin. Measurements and Main Results: Following S. pneumoniae infection, murine pulmonary sphingosine-1-phosphate levels and sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 expression were increased. Pneumonia-induced lung hyperpermeability was reduced in SphK1(-/-) mice compared with wild-type mice. Expression of sphingosine kinase 1 in macrophages recruited to inflamed lung areas in pneumonia was observed in murine and human lungs. S. pneumoniae induced the sphingosine kinase 1/sphingosine-1-phosphate system in blood-derived macrophages and enhanced sphingosine-1-phosphate receptor 2 expression in human pulmonary microvascular endothelial cell in vitro. In isolated mouse lungs, pneumolysin-induced hyperpermeability was dose dependently and synergistically increased by sphingosine-1-phosphate. This sphingosine-1-phosphate-induced increase was reduced by inhibition of sphingosine-1-phosphate receptor 2 or its downstream effector Rho-kinase. Conclusions: Our data suggest that targeting the sphingosine kinase 1-/sphingosine-1-phosphate-/sphingosine-1-phosphate receptor 2-signaling pathway in the lung may provide a novel therapeutic perspective in pneumococcal pneumonia for prevention of acute lung injury.
KW  - acute lung injury
KW  - pneumococcal pneumonia
KW  - sphingosine kinase 1
KW  - sphingosine-1-phosphate
KW  - sphingosine-1-phosphate receptor 2
Y1  - 2018
U6  - https://doi.org/10.1097/CCM.0000000000002916
SN  - 0090-3493
SN  - 1530-0293
VL  - 46
IS  - 3
SP  - e258
EP  - e267
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  -