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

Nature Medicine volume 11, pages 491–498 (2005)Cite this article

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.

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Figure 1: Lung ceramide levels are increased by VEGFR blockade.
Figure 2: Inhibition of de novo ceramide synthesis prevents VEGFR blockade–induced emphysema.
Figure 3: Ceramide augmentation triggers lung apoptosis and emphysema.
Figure 4: Self-amplification of lung ceramide synthesis.
Figure 5: Increased lung ceramide in patients with emphysema.

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Acknowledgements

The authors acknowledge the technical assistance of L. Natarajan, S.I. Ramirez, J. Skirball (cell culture and caspase-3 activity assay) and D. Rau (HPLC). We thank D. Griffin who provided the acid sphingomyelinase–deficient human fibroblasts. We thank C. Cool for providing additional normal human lung samples, and A.M.K. Choi and J.G.N. Garcia for critically reading our manuscript. Funding for these studies is from the US National Institutes of Health grant K08 HL04396; American Thoracic Society/Alpha One Foundation Research Grant; and American Lung Association Research Grant (to I.P.); US National Institutes of Health grants RO1 HL71152 (to V.N.), 1S10 RR16798 (to W.C.H.) and RO1HL66554 (to R.M.T.).

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Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, JHAAC, 4B.65, Baltimore, 21224, Maryland, USA

    Irina Petrache, Viswanathan Natarajan, Terry R Medler, Evgeny V Berdyshev & Rubin M Tuder

  2. Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University, 720 Rutland Avenue, Ross #519, Baltimore, 21205, Maryland, USA

    Lijie Zhen, Amy T Richter, Chung Cho & Rubin M Tuder

  3. Division of Allergy and Immunology, Department of Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, JHAAC, 4B.65, Baltimore, 21224, Maryland, USA

    Walter C Hubbard

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Supplementary information

Supplementary Fig. 1

Schematic representation of ceramide as an amplifying mediator in pulmonary emphysema based on the findings in the VEGFR blockade model. (PDF 118 kb)

Supplementary Fig. 2

VEGFR blockade rapidly induces apoptosis in the mouse lung. (PDF 101 kb)

Supplementary Fig. 3

De novo ceramide synthesis is necessary for the development of emphysema, preceding caspase activation. (PDF 122 kb)

Supplementary Fig. 4

Ceramide augmentation causes cell apoptosis and oxydative stress in the mouse lung. (PDF 216 kb)

Supplementary Fig. 5

ASMase regulates paracellular amplification of ceramide synthesis. (PDF 188 kb)

Supplementary Table 1

Clinical characteristics of patients who provided lung biopsy samples for ceramide analysis. (PDF 38 kb)

Supplementary Methods (PDF 28 kb)

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Petrache, I., Natarajan, V., Zhen, L. et al. Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. Nat Med 11, 491–498 (2005). https://doi.org/10.1038/nm1238

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