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: Krzysztof Kamocki, Mary Van Demark, Amanda Fisher, Natalia I Rush, Robert G Presson Jr, Walter Hubbard, Evgeny V Berdyshev, Swetlana Adamsky, Elena Feinstein, Aneta Gandjeva, Rubin M Tuder, Irina Petrache
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 48 Issue 1 Pg. 87-93 (Jan 2013) ISSN: 1535-4989 [Electronic] United States
• PMID: 23024063 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Ceramides
• DNA-Binding Proteins
• Ddit4l protein, mouse
• Transcription Factors
• Receptors, Vascular Endothelial Growth Factor

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Apoptosis (physiology)
• Ceramides (physiology)
• DNA-Binding Proteins (deficiency, genetics, physiology)
• Emphysema (etiology, pathology, physiopathology, prevention & control)
• Endothelial Cells (pathology, physiology)
• Epithelial Cells (pathology, physiology)
• Female
• Lung (pathology, physiopathology)
• Lung Compliance (physiology)
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• Oxidative Stress
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)
• Smoking (adverse effects, pathology, physiopathology)
• Transcription Factors (deficiency, genetics, physiology)