Neutral sphingomyelinase 2 is activated by cigarette smoke to augment ceramide-induced apoptosis in lung cell death.
Cigarette smoke (CS) induces a rapid, sustained upregulation of ceramide production in human bronchial epithelial cells, leading to increased apoptosis. Using loss-of-function and overexpression analyses, we show that neutral sphingomyelinase 2 (nSMase2) is required for CS-mediated ceramide generation and apoptosis. Glutathione (GSH), a crucial antioxidant in lung defense, blocks nSMase2 activity and thus inhibits apoptosis triggered by CS. We found that the exposure to CS, as with exposure to H(2)O(2), results in increased nSMase2 activation leading to ceramide generation and therefore increased apoptosis. Interestingly, exposure of cells to GSH abolishes nSMase2 activation caused by CS and leads to a decrease in CS-induced apoptosis. This suggests that the effects of CS oxidants on nSMase2 are counteracted by GSH. Our data support a model where CS induces nSMase2 activation thereby increasing membrane-sphingomyelin hydrolysis to ceramide. In turn, elevated ceramide enhances airway epithelial cell death, which causes bronchial and alveolar destruction and lung injury in pulmonary diseases.
Levy
Michal
M
Internal Medicine Respiratory Signal Transduction, University of California, School of Medicine, Davis, California 95616, USA.
Khan
Elaine
E
Careaga
Milo
M
Goldkorn
Tzipora
T
D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002518:Ceramides / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D020868:Gene Silencing / Q000187:drug effects; D005949:Glucose Oxidase / Q000378:metabolism; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008168:Lung / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000378:metabolism; D012906:Smoke; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013997:Time Factors; D014026:Nicotiana / Q000737:chemistry*; D015854:Up-Regulation / Q000187:drug effects
D002518:Ceramides; D034741:RNA, Small Interfering; D012906:Smoke; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; C491484:SMPD3 protein, human; D013108:Sphingomyelin Phosphodiesterase; D005978:Glutathione