Relationship of Inhaled Ozone Concentration to Acute Tracheobronchial Epithelial Injury, Site-specific Ozone Dose, and Glutathione Depletion in Rhesus Monkeys

Abstract

Acute pulmonary epithelial injury produced by short-term exposure to ozone varies by site within the tracheobronchial tree. To test whether this variability is related to the local dose of ozone at the tissue site or to local concentrations of glutathione, we exposed adult male rhesus monkeys for 2 h to filtered air or to 0.4 or 1.0 ppm ozone generated from 18O2. Following exposure, lungs were split into lobes and specimens were selected by microdissection so that measurements could be made on airway tissue of similar branching history, including trachea, proximal (generation one or two) and distal (generation six or seven) intrapulmonary bronchi, and proximal respiratory bronchioles. One half of the lung was lavaged for analysis of extracellular components. In monkeys exposed to filtered air, the concentration of reduced glutathione (GSH) varied throughout the airway tree, with the proximal intrapulmonary bronchus having the lowest concentration and the parenchyma having the highest concentration. Exposure to 1.0 ppm ozone significantly reduced GSH only in the respiratory bronchiole, whereas exposure to 0.4 ppm increased GSH only in the proximal intrapulmonary bronchus. Local ozone dose (measured as excess 18O) varied by as much as a factor of three in different airways of monkeys exposed to 1.0 ppm, with respiratory bronchioles having the highest concentration and the parenchyma the lowest concentration. In monkeys exposed to 0.4 ppm, the ozone dose was 60% to 70% less than in the same site in monkeys exposed to 1.0 ppm. Epithelial disruption was present to some degree in all airway sites, but not in the parenchyma, in animals exposed to 1.0 ppm ozone. The mass of mucous and ciliated cells decreased in all airways, and necrotic and inflammatory cells increased. At 0.4 ppm, epithelial injury was minimal, except in the respiratory bronchiole, where cell loss and necrosis occurred, and was 50% that found in monkeys exposed to 1.0 ppm ozone. We conclude that there is a close association between site-specific O3 dose, the degree of epithelial injury, and glutathione depletion at local sites in the tracheobronchial tree.

Volatile Organic Compounds from Pesticide Application and Contribution to Tropospheric Ozone

“…A number of investigators have observed statistically significant increases in alveolar macrophages (AM), protein, albumin, total cell counts, and polymorphonuclear monocytes (PMNs) numbers in BALF and bronchiolar epithelium of rodents, dogs, and monkeys at various time points following acute exposures to 0.2 ppm O 3 (Freed et al, 1999;Kleinman et al, 1999;Oosting et al, 1991;Plopper et al, 1998). Both monkeys and ferrets appear to be more sensitive to O 3 -induced inflammatory cell infiltration and airway epithelial injury than rodents (Sterner-Kock et al, 2000).…”

“…The most pronounced lesions occur in the centriacinar region which receives the largest O 3 dose (e.g. terminal and respiratory bronchioles in primates) (Plopper et al, 1998). Ciliated respiratory epithelium in the tracheobronchiolar region is damaged in a dose-dependent manner by repeated O 3 exposures 0.2 ppm (Castleman et al, 1980;Van Bree et al, 2001).…”

“…GSH reductase, GSH-S-transferase, and GSH peroxidase activity increased in a dose-dependent manner in centriacinar tissue following exposure to 0.12 ppm O 3 in rats, mice, and guinea pigs for 3-90 days (Dormans et al, 1999;Plopper et al, 1994). In monkeys, the site-specific reduction in GSH pool following acute O 3 exposures and the ability of different areas of the airway epithelium to replenish that pool, may be a factor in site-specific injury (Plopper et al, 1998).…”

Promotion of cardiovascular disease by exposure to the air pollutant ozone

“…Both computer simulation studies of pulmonary O 3 reactions and experimental observations bear this out, since there is not a particularly "deep" penetration of O 3 and O 3 -mediated cell injury into the lung. The primary anatomic sites of O 3 reaction in the lungs (at environmentally relevant concentrations of 0.5 ppm or less) are the airway and nasal epithelium, with small conducting airways and bronchioles a preferred reaction site, rather than more distal parenchymal alveolar epithelial cell reactions (18,20,25). Even in still-developing primate infants, episodic O 3 exposure primarily affects the morphogenesis of tracheobronchial airways and damages airway epithelial cells in terminal and respiratory bronchioles (8).…”

Gas Uptake in a Three-Generation Model Geometry During Steady Expiration: Comparison of Axisymmetric and Three-Dimensional Models

“…The axial dose distribution is different depending on the properties of the gases (Nodelman & Ultman, 1999); for example, chlorine was absorbed in upper airways and trachea, and ozone reached lower airways. Experiments were done to relate the concentration of ozone exposure and the epithelial injury in an asymmetric rhesus monkey lung (Plopper et al, 1998) and rat lung Joad et al, 2000). The distribution of tissue dose is dependent on axial dose distribution of gases in lungs, which is difficult to measure, so it is important to develop mathematical models of flow, diffusion, and reaction of reactant pollutants in the respiratory system.…”