RTP801 is required for ceramide-induced cell-specific death in the murine lung

Krzysztof Kamocki, Mary Van Demark, Amanda Fisher, Natalia I. Rush, Robert G. Presson, Walter Hubbard, Evgeny V. Berdyshev, Swetlana Adamsky, Elena Feinstein, Aneta Gandjeva, Rubin M. Tuder, Irina Petrache

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Key host responses to the stress induced by environmental exposure to cigarette smoke (CS) are responsible for initiating pathogenic effects thatmay 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 emphysemalike 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.

Original languageEnglish (US)
Pages (from-to)87-93
Number of pages7
JournalAmerican journal of respiratory cell and molecular biology
Volume48
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • Apoptosis
  • Cigarette smoke
  • Emphysema
  • Sphingolipids
  • Stress response

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

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    Kamocki, K., Van Demark, M., Fisher, A., Rush, N. I., Presson, R. G., Hubbard, W., Berdyshev, E. V., Adamsky, S., Feinstein, E., Gandjeva, A., Tuder, R. M., & Petrache, I. (2013). RTP801 is required for ceramide-induced cell-specific death in the murine lung. American journal of respiratory cell and molecular biology, 48(1), 87-93. https://doi.org/10.1165/rcmb.2012-0254OC