Nature Medicine
11, 491 - 498 (2005)
Published online: 24 April 2005; | doi:10.1038/nm1238
Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in miceIrina Petrache1, Viswanathan Natarajan1, Lijie Zhen2, Terry R Medler1, Amy T Richter2, Chung Cho2, Walter C Hubbard3, Evgeny V Berdyshev1
& Rubin M Tuder1, 21
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, JHAAC, 4B.65, Baltimore, Maryland
21224, USA. 2
Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University, 720 Rutland Avenue, Ross #519, Baltimore, Maryland
21205, USA. 3
Division of Allergy and Immunology, Department of Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, JHAAC, 4B.65, Baltimore, Maryland
21224, USA.
Correspondence should be addressed to Irina Petrache ipetra@jhmi.eduAlveolar cell apoptosis is involved in the pathogenesis of emphysema, a prevalent disease primarily caused by cigarette smoking. We report that ceramide, a second messenger lipid, is a crucial mediator of alveolar destruction in emphysema. Inhibition of enzymes controlling de novo ceramide synthesis prevented alveolar cell apoptosis, oxidative stress and emphysema caused by blockade of the vascular endothelial growth factor (VEGF) receptors in both rats and mice. Emphysema was reproduced with intratracheal instillation of ceramide in naive mice. Excessive ceramide triggers a feed-forward mechanism mediated by activation of secretory acid sphingomyelinase, as suggested by experiments with neutralizing ceramide antibody in mice and with acid sphingomyelinase−deficient fibroblasts. Concomitant augmentation of signaling initiated by a prosurvival metabolite, sphingosine-1-phosphate, prevented lung apoptosis, implying that a balance between ceramide and sphingosine-1-phosphate is required for maintenance of alveolar septal integrity. Finally, increased lung ceramides in individuals with smoking-induced emphysema suggests that ceramide upregulation may be a crucial pathogenic element and a promising target in this disease that currently lacks effective therapies.
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