title: RTP801 is required for ceramide-induced cell-specific death in the murine lung.
abstract: Key host responses to the stress induced by environmental exposure to cigarette smoke (CS) are responsible for initiating pathogenic effects that may culminate in emphysema development. CS increases lung ceramides, sphingolipids involved in oxidative stress, structural alveolar cell apoptosis, and inhibition of apoptotic cell clearance by alveolar macrophages, leading to the development of emphysema-like pathology. RTP801, a hypoxia and oxidative stress sensor, is also increased by CS, and has been recently implicated in both apoptosis and inflammation. We investigated whether inductions of ceramide and RTP801 are mechanistically linked, and evaluated their relative importance in lung cell apoptosis and airspace enlargement in vivo. As reported, direct lung instillation of either RTP801 expression plasmid or ceramides in mice triggered alveolar cell apoptosis and oxidative stress. RTP801 overexpression up-regulated lung ceramide levels 2.6-fold. In turn, instillation of lung ceramides doubled the lung content of RTP801. Cell sorting after lung tissue dissociation into single-cell suspension showed that ceramide triggers both endothelial and epithelial cell apoptosis in vivo. Interestingly, mice lacking rtp801 were protected against ceramide-induced apoptosis of epithelial type II cells, but not type I or endothelial cells. Furthermore, rtp801-null mice were protected from ceramide-induced alveolar enlargement, and exhibited improved static lung compliance compared with wild-type mice. In conclusion, ceramide and RTP801 participate in alveolar cell apoptosis through a process of mutual up-regulation, which may result in self-amplification loops, leading to alveolar damage.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indianapolis, IN 46202, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamocki
authors.forename: Mary
authors.initials: M
authors.lastname: Van Demark
authors.forename: Amanda
authors.initials: A
authors.lastname: Fisher
authors.forename: Natalia I
authors.initials: NI
authors.lastname: Rush
authors.forename: Robert G
authors.initials: RG
authors.lastname: Presson
authors.forename: Walter
authors.initials: W
authors.lastname: Hubbard
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Berdyshev
authors.forename: Swetlana
authors.initials: S
authors.lastname: Adamsky
authors.forename: Elena
authors.initials: E
authors.lastname: Feinstein
authors.forename: Aneta
authors.initials: A
authors.lastname: Gandjeva
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002518:Ceramides / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004646:Emphysema / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D005260:Female; D008168:Lung / Q000473:pathology* / Q000503:physiopathology*; D008170:Lung Compliance / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012907:Smoking / Q000009:adverse effects / Q000473:pathology / Q000503:physiopathology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002518:Ceramides; D004268:DNA-Binding Proteins; C450979:Ddit4l protein, mouse; D014157:Transcription Factors; D040262:Receptors, Vascular Endothelial Growth Factor