Apoptotic sphingolipid signaling by ceramides in lung endothelial cells

Terry R. Medler, Daniela N. Petrusca, Patty J. Lee, Walter C. Hubbard, Evgeny V. Berdyshev, Jarrett Skirball, Krzysztof Kamocki, Edward Schuchman, Rubin M. Tuder, Irina Petrache

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59 Scopus citations


The de novo pathway of ceramide synthesis has been implicated in the pathogenesis of excessive lung apoptosis and murine emphysema. Intracellular and paracellular-generated ceramides may trigger apoptosis and propagate the death signals to neighboring cells, respectively. In this study we compared the sphingolipid signaling pathways triggered by the paracellular- versus intracellular-generated ceramides as they induce lung endothelial cell apoptosis, a process important in emphysema development. Intermediate-chain length (C8:0) extracellular ceramides, used as a surrogate of paracellular ceramides, triggered caspase-3 activation in primary mouse lung endothelial cells, similar to TNF-α-generated endogenous ceramides. Inhibitory siRNA against serine palmitoyl transferase subunit 1 but not acid sphingomyelinase inhibited both C8:0 ceramide- and TNF-α (plus cycloheximide)-induced apoptosis, consistent with the requirement for activation of the de novo pathway of sphingolipid synthesis. Tandem mass spectrometry analysis detected increases in both relative andabsolute levels of C 16:0 ceramide in response to C8:0 and TNF-α treatments. These results implicate the de novo pathway of ceramide synthesis in the apoptotic effects of both paracellular ceramides and TNF-α-stimulated intracellular ceramides in primary lung endothelial cells. The serine palmitoyl synthase-regulated ceramides synthesis may contribute to the amplification of pulmonary vascular injury inducedby excessive ceramides.

Original languageEnglish
Pages (from-to)639-646
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Issue number6
StatePublished - 1 Jun 2008


  • Apoptosis
  • Cytokines
  • Lung
  • Signaling
  • Sphingolipids


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