Continual exposure to ozone alters the metabolic homeostasis of the respiratory system. Sites within the respiratory tract which are susceptible to injury with initial exposure develop resistance upon continued exposure. This project will define the impact these cellular and metabolic alterations have on the lung's ability to respond to bioactivated, environmental contaminants, such as nitronaphthalene. The pulmonary cytotoxicity of nitronaphthalene, a Clara cell cytotoxicant, depends upon cytochrome P-450 monooxygenase-mediated metabolism. Nitroaromatics such as ntironaphthalene are major components of diesel exhaust emissions. Humans living in urban areas are exposed simultaneously to both nitroaromatics (and other P-450 mediated cytotoxicants) and to high levels of oxidant air pollutants. Previous studies indicate that exposure to ozone produces marked alterations in P-450 monooxygenase activity. Short-term ozone exposure results in focal injury to the centriacinus, a target site shared by nitronaphthalene. Long term exposure to ozone produces a reorganized cell population tolerant to further oxidant injury. However, there is little information about the potential effects of exposure to one of these classes of agents on the response of the lung to the other. These studies will evaluate the metabolic and cellular basis of the responses of target areas in the lung to short and long-term exposure to ozone combined with acute exposures to ntironaphthalene.
The specific aims are to define: (1) the anatomic subcompartment and cellular modifications to the pulmonary P-450 system resulting from acute oxidant injury; (2) the metabolic pathways for activation and detoxification of 1- nitronaphthalene within target and non-target cell populations (3) the impact of short-term ozone exposure on the acute Clara cell toxicity of 1- nitronaphthalene; (4) the mechanisms by which long-term exposure to ozone, i.e., exposures which produce tolerance, impacts on the acute and chronic injury produced by nitronaphthalene; (5) the alterations in the P-450 system and in glutathione pools in target and non-target cells following development of tolerance from continual exposure to ozone. Responses will be compared in two species: one which is relatively insensitive to ozone, the laboratory rat, and another which is more sensitive to ozone injury, the rhesus monkey. The cytotoxicity and metabolism studies will be conducted on animals exposed in vivo. The cellular and metabolic mechanisms will be evaluated in airway cells from target and non-target regions of the lung which are isolated by microdissection and in alveolar type 2 cells isolated from exposed and unexposed animals. These studies will provide needed information regarding the impact which exposure to these two pollutants will have on the homeostasis of the respiratory system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
2P01ES000628-22A1
Application #
3733571
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of California Davis
Department
Type
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
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