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Tobacco smoke oxidant‐induced apoptosis is mediated by nSMase2 in lung epithelial cells
Author(s) -
Levy Michal,
Khan Elaine,
Lanir Roni,
Castillo Sianna S,
Goldkorn Tzipora
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1081-b
Subject(s) - ceramide , sphingomyelin , acid sphingomyelinase , apoptosis , sphingomyelin phosphodiesterase , oxidative stress , microbiology and biotechnology , lung , lipid signaling , chemistry , immunology , medicine , inflammation , cancer research , biology , biochemistry , cholesterol
Cigarette smoking (CS) is the main cause for emphysema, a pathologic state in the lung characterized by the destruction of alveolar walls. Ceramide, a second messenger lipid, is a critical mediator of alveolar destruction in lung diseases such as chronic obstructive pulmonary diseases (COPD), which consist of emphysema and chronic bronchitis. We have shown that CS induces rapid, sustained ceramide up‐regulation in human airway epithelial (HAE) cells in a dose dependent manner. We have also observed that CS induced ceramide to a similar extent as hydrogen peroxide (H2O2), a classical stimulus of ceramide generation in HAE cells and an oxidant known to be elevated in the breath or serum of patients with COPD. We showed that the amount of H2O2 found in cell culture medium exposed to CS increases with time. We demonstrated by loss‐of‐function analysis or by overexpression that nSMase2, but not aSMase, activity is required for CS‐mediated ceramide generation and apoptosis. Furthermore we observed that nSMase2 is trafficking similarly under both CS exposure and under oxidative‐stress, suggesting that the regulation of nSMase2 may mainly occur at the level of subcellular localization. Following either CS or H2O2 exposure, nSMase2 was found localized to the plasma membrane, where it can convert sphingomyelin to ceramide. These studies suggest that at the molecular level, there is direct coupling between CS oxidative stress and the ceramide pathway, via a sphingomyelinase (SMase). Under CS exposure a lung SMase, nSMase2, is activated and displays continuous ceramide generation and pro‐apoptotic signaling, thus leading to the pathological apoptosis that causes lung injury.