Published ahead of print on January 10, 2008, doi:10.1165/rcmb.2007-0274OC Am. J. Respir. Cell Mol. Biol., Volume 38, Number 6, June 2008, 639-646 A more recent version of this article appeared on June 1, 2008
Submitted on July 19, 2007 Apoptotic Sphingolipid Signaling by Ceramides in Lung Endothelial CellsTerry R Medler1,1 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Indiana University, Indianapolis, IN, USA, 3 Section of Pulmonary and Critical Care, Yale University School of Medicine, New Haven, CT, USA, 4 Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 5 Division of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA, 6 Division of Molecular Genetics, Mount Sinai School of Medicine, New York, NY, USA, 7 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 8 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Indiana University, Indianapolis, IN, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA * To whom correspondence should be addressed. E-mail: ipetrach{at}iupui.edu.
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, utilized as a surrogate of paracellular ceramides, triggered caspase-3 activation in primary mouse lung endothelial cells, similar to TNF
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-generated endogenous ceramides. Inhibitory siRNA against serine palmitoyl transferase subunit 1 but not acid sphingomyelinase inhibited both C8:0 ceramide- and TNF
