The health effects of chronic ozone exposure are unknown. Because of obvious ethical problems, chronic exposures of human volunteers to ozone in controlled environmental chambers will not be done. Therefore, the health risks from chronic ozone exposure must be estimated by using data from chronic animal exposure studies. Thus, the proposed research will investigate the effects of chronic ozone exposures on the mucous apparatus in the upper and lower airways of the rats. Rats will be exposed 8 h/day, 7 days/wk for 1, 3, 6, or 12 mo to 0.25, 0.5, or 1 ppm ozone. These animals will be sacrificed immediately (Specific Aim 1), and at 1 mo, 3 mo, or 6 mo after the end of the exposure (Specific Aim 2) to monitor the persistence of the pathology. Nasal and lung lavage fluids will be analyzed to determine the amount of secreted mucin using an enzyme-linked immunosorbant assay. Also, the amount of intracellularly stored mucosubstances in nasal and pulmonary airways will be estimated using histochemistry and morphometry. Mucin gene expression in nose and lung will be assessed by quantifying airway mucin mRNA. Using the same methods, a third Specific Aim will be to determine the effects of ozone exposures on the recovery of rat pulmonary airways from a hypersecretory condition similar to that in patients with chronic bronchitis or asthma. In addition, we will determine if anti-inflammatory drugs speed the recovery from ozone-induced mucous cell metaplasia (Specific Aim 4). The proposed studies will define 1) this airway epithelial lesion induced by chronic ozone, 2) the time course of recovery from this lesion, 3) the effects of ozone on hypersecretory airways, and 4) the effectiveness of anti- inflammatory drugs in attenuating the lesion. Further, our ability to determine the time points at which mucin synthesis (mRNA induction) and hypersecretion (mucin release into airway lumens) occur will open the way for future studies into mechanisms mediating these changes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL051712-02
Application #
2228619
Study Section
Special Emphasis Panel (SRC)
Project Start
1993-08-01
Project End
1997-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Michigan State University
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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Cho, H Y; Hotchkiss, J A; Harkema, J R (1999) Inflammatory and epithelial responses during the development of ozone-induced mucous cell metaplasia in the nasal epithelium of rats. Toxicol Sci 51:135-45
Fanucchi, M V; Harkema, J R; Plopper, C G et al. (1999) In vitro culture of microdissected rat nasal airway tissues. Am J Respir Cell Mol Biol 20:1274-85
Fanucchi, M V; Hotchkiss, J A; Harkema, J R (1998) Endotoxin potentiates ozone-induced mucous cell metaplasia in rat nasal epithelium. Toxicol Appl Pharmacol 152:1-9
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Harkema, J R; Barr, E B; Hotchkiss, J A (1997) Responses of rat nasal epithelium to short- and long-term exposures of ozone: image analysis of epithelial injury, adaptation and repair. Microsc Res Tech 36:276-86