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Tobacco oxidants and the ceramide path in lung cell death

Institution: University of California, Davis
Investigator(s): Tzipora Goldkorn, BSc, MSc, Ph.D.
Award Cycle: 1999 (Cycle 8) Grant #: 8RT-0098 Award: $427,613
Subject Area: Pulmonary Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
It is well known that cigarette smoking exerts a host of adverse effects on bronchial epithelial cells, leading to pulmonary disease. Cigarette smoke is known to contain abundant free radical species and reactive oxidants. There is ample evidence that these reactive oxidants play a role in cigarette smoke-induced adverse health consequences. The mechanism for the increased lung disease from cigarette smoke is poorly understood, but the dire consequences are presumed to manifest due to the absorption of tobacco smoke reactive oxidants, which affect lung epithelial cell function. Although a link between reactive oxidants and epithelial injury has been established, the cellular mechanisms leading to epithelial dysfunction are poorly defined.

The goal of the proposed project is to determine how exposure of lung epithelial cells to reactive oxidants may change their molecular mechanism of growth and death. We propose to investigate the cellular pathway of ceramide, a cell sphingolipid which regulates the process of programmed cell death (apoptosis), and to characterize the effects of reactive oxidants of tobacco smoke, such as H2O2 and ONOO-, on ceramide signaling and the consequential apoptosis in the lung epithelium.

The results of theses studies will be informative for how lung epithelial cells perceive, discriminate, and respond to oxidative stress, and will determine the contribution of specific molecular changes induced by reactive oxidants to lung epithelium injury.

Understanding the mechanism(s) of tobacco oxidants- induced changes in lung epithelial cells is crucial to the development of therapeutic and pharmacological strategies to block the destructive properties of tobacco reactive oxidants, thereby reducing damage to the airway epithelium system of cigarette smokers. These therapies could benefit both men and women, and specifically young women, who continue to initiate smoking at dispropotionally higher rates than males and fail to accurately perceive lung disease as a leading health threat to California and US women.
Publications

Ceramide path in human lung cell death
Periodical: American Journal of Respiratory Cell and Molecular Biology Index Medicus:
Authors: Chan C, Goldkorn T ART
Yr: 2000 Vol: 22 Nbr: 4 Abs: Pg: 460-468

Ceramide-mediated apoptosis in lung epithelial cells is regulated by gluthathione.
Periodical: American Journal of Respiratory Cell and Molecular Biology Index Medicus:
Authors: Lavrentiadou SN, Chan C, Kawcak T, Ravid T, Tsaba A, van der Vliet A, Rasooly R, and et al ART
Yr: 2001 Vol: 25 Nbr: Abs: Pg: 676-684

Ceramide accumulation precedes caspase-3 activation during apoptosis of A549 human lung adenocarcinoma cells.
Periodical: American Journal of Physiology. Lung Cell Molecular Physiology. Index Medicus:
Authors: Ravid T, Tsaba A, Gee P, Rasooly R, Medina EA, Goldkorn T ART
Yr: 2003 Vol: 284 Nbr: 6 Abs: Pg: L1082-1092

Ceramide-mediated apoptosis in lung epithelial cells is regulated by glutathione.
Periodical: American Journal of Respiratory Cell and Molecular Biology Index Medicus:
Authors: Lavrentiadou S, Chan C, Kawcak T, Ravid T, Tsaba A, van der Vliet A, Rasooly R, Goldkorn T ART
Yr: 2001 Vol: 25 Nbr: Abs: Pg: 676-684

Ceramide path in human lung cell death.
Periodical: American Journal of Respiratory Cell and Molecular Biology Index Medicus:
Authors: Chan C, Goldkorn T ART
Yr: 2000 Vol: 22 Nbr: 4 Abs: Pg: 460-468

H202 acts on cellular membranes to generate ceramide signaling and initiate apoptosis in tracheobronchial epithelial cells.
Periodical: Journal of Cell Science Index Medicus:
Authors: Goldkorn T, Balaban N, Shannon M, Chea V, Matsukuma K, Gilchrist D, Wang H, Chan C ART
Yr: 1998 Vol: 111 Nbr: 21 Abs: Pg: 3209-3220