Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice

Irina Petrache, Viswanathan Natarajan, Lijie Zhen, Terry R. Medler, Amy T. Richter, Chung Cho, Walter C. Hubbard, Evgeny V. Berdyshev, Rubin M. Tuder

Research output: Contribution to journalArticle

Abstract

Alveolar 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.

Original languageEnglish (US)
Pages (from-to)491-498
Number of pages8
JournalNature Medicine
Volume11
Issue number5
DOIs
StatePublished - May 2005

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Ceramides
Emphysema
Up-Regulation
Apoptosis
Lung
Alveolar Epithelial Cells
Sphingomyelin Phosphodiesterase
Smoking
Vascular Endothelial Growth Factor Receptor
Acids
Second Messenger Systems
Oxidative stress
Neutralizing Antibodies
Fibroblasts
Metabolites
Tobacco Products
Oxidative Stress
Rats
Maintenance
Lipids

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Petrache, I., Natarajan, V., Zhen, L., Medler, T. R., Richter, A. T., Cho, C., ... Tuder, R. M. (2005). Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. Nature Medicine, 11(5), 491-498. https://doi.org/10.1038/nm1238

Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. / Petrache, Irina; Natarajan, Viswanathan; Zhen, Lijie; Medler, Terry R.; Richter, Amy T.; Cho, Chung; Hubbard, Walter C.; Berdyshev, Evgeny V.; Tuder, Rubin M.

In: Nature Medicine, Vol. 11, No. 5, 05.2005, p. 491-498.

Research output: Contribution to journalArticle

Petrache, I, Natarajan, V, Zhen, L, Medler, TR, Richter, AT, Cho, C, Hubbard, WC, Berdyshev, EV & Tuder, RM 2005, 'Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice', Nature Medicine, vol. 11, no. 5, pp. 491-498. https://doi.org/10.1038/nm1238
Petrache I, Natarajan V, Zhen L, Medler TR, Richter AT, Cho C et al. Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. Nature Medicine. 2005 May;11(5):491-498. https://doi.org/10.1038/nm1238
Petrache, Irina ; Natarajan, Viswanathan ; Zhen, Lijie ; Medler, Terry R. ; Richter, Amy T. ; Cho, Chung ; Hubbard, Walter C. ; Berdyshev, Evgeny V. ; Tuder, Rubin M. / Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. In: Nature Medicine. 2005 ; Vol. 11, No. 5. pp. 491-498.
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