title: Ceramide synthases expression and role of ceramide synthase-2 in the lung: insight from human lung cells and mouse models.
abstract: Increases in ceramide levels have been implicated in the pathogenesis of both acute or chronic lung injury models. However, the role of individual ceramide species, or of the enzymes that are responsible for their synthesis, in lung health and disease has not been clarified. We now show that C24- and C16-ceramides are the most abundant lung ceramide species, paralleled by high expression of their synthetic enzymes, ceramide synthase 2 (CerS2) and CerS5, respectively. Furthermore, the ceramide species synthesis in the lung is homeostatically regulated, since mice lacking very long acyl chain C24-ceramides due to genetic deficiency of CerS2 displayed a ten-fold increase in C16-ceramides and C16-dihydroceramides along with elevation of acid sphingomyelinase and CerS5 activities. Despite relatively preserved total lung ceramide levels, inhibition of de novo sphingolipid synthesis at the level of CerS2 was associated with significant airflow obstruction, airway inflammation, and increased lung volumes. Our results suggest that ceramide species homeostasis is crucial for lung health and that CerS2 dysfunction may predispose to inflammatory airway and airspace diseases.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indianapolis, Indiana, USA. ipetrach@iu.edu
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamocki
authors.forename: Christophe
authors.initials: C
authors.lastname: Poirier
authors.forename: Yael
authors.initials: Y
authors.lastname: Pewzner-Jung
authors.forename: Elad L
authors.initials: EL
authors.lastname: Laviad
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Schweitzer
authors.forename: Mary
authors.initials: M
authors.lastname: Van Demark
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Justice
authors.forename: Walter C
authors.initials: WC
authors.lastname: Hubbard
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
mesh_terms: D000818:Animals; D002460:Cell Line; D002518:Ceramides / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006706:Homeostasis; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D011650:Pulmonary Alveoli / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D051049:Sphingosine N-Acyltransferase / Q000172:deficiency / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: D002518:Ceramides; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; C438311:CERS2 protein, human; C580723:Cers2 protein, mouse; D051049:Sphingosine N-Acyltransferase