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ToxSci Advance Access published online on June 12, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg156
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received January 24, 2003; accepted May 19, 2003
© 2003 Society of Toxicology

Respiratory Toxicology

Repeated Inhalation Exposures of the Bioactivated Cytotoxicant Naphthalene (NA) Produce Airway Specific Clara Cell Tolerance in Mice

Jay A. A. West 1*, Laura S. Van Winkle 1, Dexter Morin 2, Chad A. Fleschner 1, Henry Jay Forman 3, Alan R. Buckpitt 2, and Charles G. Plopper 1

1 Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, 95616
2 Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, 95616
3 Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, 317 Ryals (1665 University Blvd.), Birmingham, AL 35294-0022

* To whom correspondence should be addressed. E-mail: jawest{at}sandia.gov.


  Abstract

Repeated exposures to bioactivated cytotoxicants, such as naphthalene (NA), render the target population (Clara cells) resistant to further injury through a glutathione dependent mechanism. The current studies were designed to test the hypothesis that the mechanism for tolerance is localized in Clara cells. We used three approaches to test this hypothesis. First, using airway explants from tolerant mice maintained in culture, we sought to determine if the mechanism of Clara cell tolerance was airway specific. Second, using inhalation as the route of exposure, we sought to determine if Clara cells at all airways levels become tolerant to repeated inhalation exposures of NA. Third, by measuring {gamma}-Glutamylcysteine synthetase ({gamma}-GCS) activity and expression we aimed to determine if tolerance to inhaled NA resulted from shifts in phase II metabolism. Our results indicate that Clara cells in explants from tolerant mice remained tolerant to NA injury in culture. When mice were exposed to repeated inhalation exposures of NA (15 ppm), we found Clara cells at all airway levels became tolerant. Expression and activity analysis revealed {gamma}-GCS, the rate-limiting enzyme in glutathione synthesis, is induced in tolerant Clara cells. Buthionine sulfoximine, a {gamma}-GCS inhibitor, was able to eliminate the resistance of these tolerant cells. We conclude: 1) the mechanism of NA tolerance in Clara cells is airway specific, 2) the specific mechanism allows Clara cells to become tolerant to NA vapor at levels relevant to human exposure, and 3) the mechanism of tolerance to inhaled NA is highly dependent on induction of the catalytic enzyme, {gamma}-GCS.


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J. B. Morris and A. R. Buckpitt
Upper Respiratory Tract Uptake of Naphthalene
Toxicol. Sci., October 1, 2009; 111(2): 383 - 391.
[Abstract] [Full Text] [PDF]


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