Superoxide dismutase protects against apoptosis and alveolar enlargement induced by ceramide

Irina Petrache, Terry R. Medler, Amy T. Richter, Krzysztof Kamocki, Ugonma Chukwueke, Lijie Zhen, Yuan Gu, Jeremy Adamowicz, Kelly S. Schweitzer, Walter C. Hubbard, Evgeny V. Berdyshev, Giuseppe Lungarella, Rubin M. Tuder

Research output: Contribution to journalArticle

Abstract

The molecular events leading to emphysema development include generation of oxidative stress and alveolar cell apoptosis. Oxidative stress upregulates ceramides, proapoptotic signaling sphingolipids that trigger further oxidative stress and alveolar space enlargement, as shown in an experimental model of emphysema due to VEGF blockade. As alveolar cell apoptosis and oxidative stress mutually interact to mediate alveolar destruction, we hypothesized that the oxidative stress generated by ceramide is required for its pathogenic effect on lung alveoli. To model the direct lung effects of ceramide, mice received ceramide intratracheally (Cer12:0 or Cer8:0; 1 mg/kg) or vehicle. Apoptosis was inhibited with a general caspase inhibitor. Ceramide augmentation shown to mimic levels found in human emphysema lungs increased oxidative stress, and decreased, independently of caspase activation, the lung superoxide dismutase activity at 48 h. In contrast to their wild-type littermates, transgenic mice overexpressing human Cu/Zn SOD were significantly protected from ceramide-induced superoxide production, apoptosis, and air space enlargement. Activation of lung acid sphingomyelinase in response to ceramide treatment was abolished in the Cu/Zn SOD transgenic mice. Since cigarette smoke-induced emphysema in mice is similarly ameliorated by the Cu/Zn SOD overexpression, we hypothesized that cigarette smoke may induce ceramides in the mouse lung. Utilizing tandem mass spectrometry, we documented increased lung ceramides in adult mice exposed to cigarette smoke for 4 wk. In conclusion, ceramide-induced superoxide accumulation in the lung may be a critical step in ceramide's proapoptotic effect in the lung. This work implicates excessive lung ceramides as amplifiers of lung injury through redox-dependent mechanisms.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume295
Issue number1
DOIs
StatePublished - Jul 2008

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Ceramides
Superoxide Dismutase
Apoptosis
Lung
Oxidative Stress
Emphysema
Smoke
Tobacco Products
Alveolar Epithelial Cells
Superoxides
Transgenic Mice
Sphingomyelin Phosphodiesterase
Sphingolipids
Caspase Inhibitors
Lung Injury
Caspases
Tandem Mass Spectrometry
Vascular Endothelial Growth Factor A
Oxidation-Reduction
Theoretical Models

Keywords

  • Cell death
  • Lung
  • Oxidative stress
  • Sphingolipids

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology

Cite this

Superoxide dismutase protects against apoptosis and alveolar enlargement induced by ceramide. / Petrache, Irina; Medler, Terry R.; Richter, Amy T.; Kamocki, Krzysztof; Chukwueke, Ugonma; Zhen, Lijie; Gu, Yuan; Adamowicz, Jeremy; Schweitzer, Kelly S.; Hubbard, Walter C.; Berdyshev, Evgeny V.; Lungarella, Giuseppe; Tuder, Rubin M.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 295, No. 1, 07.2008.

Research output: Contribution to journalArticle

Petrache, I, Medler, TR, Richter, AT, Kamocki, K, Chukwueke, U, Zhen, L, Gu, Y, Adamowicz, J, Schweitzer, KS, Hubbard, WC, Berdyshev, EV, Lungarella, G & Tuder, RM 2008, 'Superoxide dismutase protects against apoptosis and alveolar enlargement induced by ceramide', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 295, no. 1. https://doi.org/10.1152/ajplung.00448.2007
Petrache, Irina ; Medler, Terry R. ; Richter, Amy T. ; Kamocki, Krzysztof ; Chukwueke, Ugonma ; Zhen, Lijie ; Gu, Yuan ; Adamowicz, Jeremy ; Schweitzer, Kelly S. ; Hubbard, Walter C. ; Berdyshev, Evgeny V. ; Lungarella, Giuseppe ; Tuder, Rubin M. / Superoxide dismutase protects against apoptosis and alveolar enlargement induced by ceramide. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2008 ; Vol. 295, No. 1.
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