title: Superoxide dismutase protects against apoptosis and alveolar enlargement induced by ceramide.
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 (Cer(12:0) or Cer(8:0); 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.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Occupational Medicine, Indiana University, Indianapolis, Indiana 46202-5120, USA. ipetrach@iupui.edu
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
authors.forename: Terry R
authors.initials: TR
authors.lastname: Medler
authors.forename: Amy T
authors.initials: AT
authors.lastname: Richter
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamocki
authors.forename: Ugonma
authors.initials: U
authors.lastname: Chukwueke
authors.forename: Lijie
authors.initials: L
authors.lastname: Zhen
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gu
authors.forename: Jeremy
authors.initials: J
authors.lastname: Adamowicz
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Schweitzer
authors.forename: Walter C
authors.initials: WC
authors.lastname: Hubbard
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Berdyshev
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lungarella
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002518:Ceramides / Q000633:toxicity*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D011650:Pulmonary Alveoli / Q000201:enzymology* / Q000473:pathology; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D012907:Smoking / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013108:Sphingomyelin Phosphodiesterase / Q000096:biosynthesis / Q000235:genetics; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism
chemical_list: D002518:Ceramides; C000606290:SOD1 protein, human; D013481:Superoxides; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D013108:Sphingomyelin Phosphodiesterase