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PAF-mediated pulmonary edema: a new role for acid sphingomyelinase and ceramide

Abstract

Platelet-activating factor (PAF) induces pulmonary edema and has a key role in acute lung injury (ALI). Here we show that PAF induces pulmonary edema through two mechanisms: acid sphingomyelinase (ASM)-dependent production of ceramide, and activation of the cyclooxygenase pathway. Agents that interfere with PAF-induced ceramide synthesis, such as steroids or the xanthogenate D609, attenuate pulmonary edema formation induced by PAF, endotoxin or acid instillation. Our results identify acid sphingomyelinase and ceramide as possible therapeutic targets in acute lung injury.

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Figure 1: ASM mediates PAF-induced edema.
Figure 2: PAF increases pulmonary ceramide content.
Figure 3: Ceramide causes pulmonary edema.
Figure 4: Ceramide-specific antisera selectively reduce PAF-induced edema formation.
Figure 5: Attenuation of PAF-induced ceramide and edema formation.
Figure 6: D609 attenuates edema formation in models of ALI.

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Acknowledgements

This study was supported by Deutsche Forschungsgemeinschaft grants SFB 367/A9 to S.U., SFB 367/C9 to S.E., SFB 415/A11 to S.S. and DFG Gu 335/10-2/3 to E.G. We thank S. Schnell (Borstel) and F. Seel (Borstel) for technical assistance.

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Correspondence to Stefan Uhlig.

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H.B. is the managing director of Glycobiotech GmbH, from which the IgM-enriched mouse serum against ceramide was obtained. The monoclonal antibody was obtained from Alexis.

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Göggel, R., Winoto-Morbach, S., Vielhaber, G. et al. PAF-mediated pulmonary edema: a new role for acid sphingomyelinase and ceramide. Nat Med 10, 155–160 (2004). https://doi.org/10.1038/nm977

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