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Vol. 294, Issue 2, 516-523, August 2000

Elevated Airway GSH Resynthesis Confers Protection to Clara Cells from Naphthalene Injury in Mice Made Tolerant by Repeated Exposures1

Jay A. A. West, Alan R. Buckpitt and Charles G. Plopper

Department of Anatomy, Physiology, and Cell Biology (J.A.A.W., C.G.P.) and Department of Molecular Biosciences (A.R.B.), School of Veterinary Medicine, University of California, Davis, California

Repeated exposures to Clara cell cytotoxicants, such as naphthalene (NA), render target cell populations resistant to further acute injury. Previous studies suggest that alterations in bioactivation enzymes in target sites (bronchioles) of tolerant mice are insufficient to account for the marked reduction in susceptibility. Mice were made tolerant by seven daily injections of NA. GSH in the terminal airways was 2.7-fold greater in tolerant mice than in vehicle controls and a NA (300 mg/kg) challenge dose did not produce injury. Tolerant mice, allowed to recuperate for 96 h after the seventh NA injection, were again susceptible to NA injury, and terminal airway GSH levels had declined to control levels. To determine whether alterations in GSH resynthesis account for tolerance, the activity of gamma -glutamylcysteine synthetase (gamma -GCS) was measured or mice were treated with a combination of buthionine sulfoximine (BSO), a gamma -GCS inhibitor, and NA. gamma -GCS activity was elevated in resistant airways of tolerant mice. Tolerant mice treated with both BSO and NA appeared as susceptible to injury as NA-challenged controls. We conclude that GSH is critical for Clara cell resistance to NA injury in tolerant mice because: 1) GSH levels in target airways from NA-tolerant animals are elevated; 2) after a 96-h recuperation period, tolerant mice had lower GSH levels and are again susceptible to NA injury; 3) alterations in the activity of gamma -GCS correspond with changes in susceptibility to NA injury; and 4) inhibition of gamma -GCS with BSO increases susceptibility to NA injury in tolerant mice.

1 Research funding was provided by National Institute of Environmental Health Sciences (NIEHS) Grants ES 04311, ES06700, and ES04699. University of California, Davis, is an NIEHS Center for Environmental Health Sciences (ES05707), and support for core facilities provided by the Center and used in this work is gratefully acknowledged.

0022-3565/00/2942-0516$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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