title: Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice.
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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, JHAAC, 4B.65, Baltimore, Maryland 21224, USA. ipetra@jhmi.edu <ipetra@jhmi.edu>
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Lijie
authors.initials: L
authors.lastname: Zhen
authors.forename: Terry R
authors.initials: TR
authors.lastname: Medler
authors.forename: Amy T
authors.initials: AT
authors.lastname: Richter
authors.forename: Chung
authors.initials: C
authors.lastname: Cho
authors.forename: Walter C
authors.initials: WC
authors.lastname: Hubbard
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Berdyshev
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004646:Emphysema / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D037341:Fumonisins / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D051102:Serine C-Palmitoyltransferase; D012907:Smoking / Q000009:adverse effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D002518:Ceramides; D005229:Fatty Acids, Monounsaturated; D037341:Fumonisins; D008246:Lysophospholipids; D042461:Vascular Endothelial Growth Factor A; C060506:sphingosine 1-phosphate; C056933:fumonisin B1; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D000217:Acyltransferases; C495089:SPTLC2 protein, human; D051102:Serine C-Palmitoyltransferase; C495088:Sptlc1 protein, mouse; D013110:Sphingosine; C001996:thermozymocidin