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Fenretinide causes emphysema, which is prevented by sphingosine 1-phoshate
Masanori Yasuo1, Shiro Mizuno, Jeremy Allegood
1Pulmonary and Critical Care Medicine Division and Victoria Johnson Center for Obstructive Lung Diseases, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Plos One
|January 18, 2013
Summary
Increased ceramide causes emphysema by inducing cell death and suppressing HIF-1α. Sphingosine 1-phosphate (S1P) counteracts this by restoring the ceramide-S1P balance and increasing HIF-1α, thus protecting against emphysema.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Biochemistry
Background:
- Sphingolipids, particularly ceramide, are implicated in emphysema development.
- Mechanisms linking ceramide to pulmonary emphysema remain incompletely understood.
- Experimental models show elevated ceramide levels in emphysema.
Purpose of the Study:
- To investigate the mechanisms of ceramide-induced pulmonary emphysema.
- To determine if sphingosine 1-phosphate (S1P) can counteract fenretinide-induced emphysema.
- To analyze the effects of ceramide and S1P on key molecular pathways in the lungs.
Main Methods:
- Rats were treated with fenretinide (ceramide inducer) and/or S1P.
- Lung tissues were analyzed for alveolar structure, apoptosis (caspase-3), and protein expression (HIF-1α, VEGF, HDAC2, Nrf2).
- Lipid levels (ceramide, dihydroceramide, S1P, dihydro-S1P) were quantified using mass spectrometry.
Main Results:
- Fenretinide increased alveolar airspace, apoptosis, and dihydroceramide, while decreasing HIF-1α and VEGF.
- S1P treatment prevented fenretinide-induced emphysema, normalized ceramide-S1P balance, and restored HIF-1α, VEGF, HDAC2, and Nrf2 expression.
- S1P increased phosphorylated sphingosine kinase 1, suggesting a role in its protective effects.
Conclusions:
- Increased de novo ceramide production drives emphysema via alveolar cell apoptosis and HIF-1α suppression.
- S1P rebalances sphingolipid metabolism and enhances HIF-1α expression, offering a protective effect against ceramide-induced emphysema.
- S1P treatment salvages fenretinide-induced emphysema in a rat model by modulating key molecular pathways.
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