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PubMedDate not supplied

Safety of ozonated solution as an antiseptic of the ocular surface prior to ophthalmic surgery.

PURPOSE: To evaluate the safety of an ozonated solution as an antiseptic of the ocular surface prior to ophthalmic surgery. METHODS: In experiment 1, a primary culture of rabbit corneal epithelium was established. Then, 0, 4 and 10 ppm ozonated solution and 1.25% povidone-iodine, respectively, were applied to confluent cells on collagen-coated filter inserts (Millicell-CM) for 10 min followed by replacement with fresh medium. The transepithelial electrical resistance (TER), which is a good indicator of cell barrier function, was sequentially measured for 30 min. In experiment 2, adult pigmented rabbit eyes were washed with 20 ml of 4 ppm ozonated solution, 1.25% povidone-iodine solution or saline. Slitlamp examinations were performed before and after washing. RESULTS: In experiment 1, 4 ppm ozonated solution did not change the TER as compared with the control. 10 ppm ozonated solution and 1.25% povidone-iodine similarly reduced the TER values significantly as compared with those of the control and 4 ppm ozonated solution. In experiment 2, 4 ppm ozonated solution and saline showed mild superficial punctate keratitis (SPK) in 8.3% of eyes. However, 1.25% povidone-iodine resulted in mild SPK in 17% of eyes and moderate SPK in 25% of eyes. The prevalence of SPK between two groups was significantly different (p = 0.03). CONCLUSION: Ozonated solution may be safe and a useful antiseptic of the ocular surface prior to ophthalmic surgery.

Animals↗
PubMed1996

Ozone enhances the uptake of mineral particles by tracheobronchial epithelial cells in organ culture.

We have previously shown that the basal uptake of mineral particles by tracheobronchial epithelial cells in organ culture is mediated in part by active oxygen species (AOS) and can be greatly augmented by exposure to cigarette smoke, a concentrated source of AOS, and other radicals. We hypothesized that ozone, another generator of AOS in tissues, might have the same effect. To test this hypothesis, tracheal explants were exposed to room air (control) or ozone in varying concentrations from 0.01 to 1.0 ppm for 10 min, and subsequently to a suspension of either amosite asbestos or titanium dioxide (rutile) for 1 h. Explants were then transferred to an air/CO2 incubator for 1 wk to allow particle uptake to occur, and uptake was determined by morphometry. We found that ozone exposure increased the uptake of both asbestos and titanium dioxide in a dose-response fashion; this effect appeared at lower exposure levels and was more marked with titanium dioxide than with amosite. The ozone effect could be prevented by addition of catalase but not superoxide dismutase to the particle suspension, or by preincubation of the particles with deferoxamine. These observations indicate that ozone can directly increase uptake of mineral particles by tracheobronchial epithelial cells; this effect occurs with brief exposures at very low ozone levels and appears to be mediated by hydrogen peroxide and possibly by hydroxyl radical. These findings support the general hypothesis that AOS are important mediators of epithelial particle uptake in many different settings. Enhanced uptake may be one of the mechanisms by which ozone impairs particle clearance from the lung and may play a role in the increased morbidity seen in populations with exposure to high levels of both ozone and atmospheric particulates.

Animals↗
PubMed1996

Effect of ambient ozone exposure on lung function in farm workers.

Effects of ozone exposure on outdoor farm workers in the Fraser Valley of British Columbia, Canada, were investigated. Fifty-eight workers underwent spirometry daily before and after each 8- to 14-h workday from June 23 to August 26, 1993. The mean daily maximum (1 h) ambient ozone concentration was 40 ppb (range: 13 to 84 ppb). Concentrations of acid aerosols and fine particulates, potential confounders of ozone effects, were very low. In individual regressions of evening FEV1 and FVC on maximum daily ozone concentration, 47 of 53 workers with valid data (46 of 53 for FVC) had negative slopes. The average slopes (weighted by the inverse SE of the regression coefficients) were -3.3 and -4.7 ml for FEV1 and FVC, respectively, for each ppb increase in ozone (p < 0.001). Following correction for an individual's mean lung function level, date, and temperature, regression of either the afternoon or the daily change (afternoon-morning) corrected for the morning measurement of FEV1 and FVC on ozone showed similar magnitudes of effect. These associations were still apparent on the following morning, suggesting a persistent ozone effect. These results indicate that exposure of a population of outdoor workers to ambient ozone concentrations below 85 ppb is associated with decreased lung function over the day, which persists to the following day.

Adult↗
PubMed1997

Ozone responsiveness in smokers and nonsmokers.

Short-term exposure to ozone causes decrements in lung function, but predictors of responsiveness remain largely unknown. Ninety healthy volunteers (56 never-smokers, age [mean +/- SD] 25 +/- 4 yr; 34 current smokers, 13 +/- 9 pack-yr, age 28 +/- 1 yr) were exposed to 0.22 ppm ozone for 4 h, with exercise, in an environmental chamber. We measured spirometry and specific airway conductance before, during, and immediately after exposure, and assessed symptoms by questionnaire. Smokers experienced a smaller increase in respiratory symptoms following exposure to ozone than did nonsmokers. Decrements in FEV1 were significantly less than for smokers than for nonsmokers (p = 0.0013). Ozone responsiveness (> 15% fall in FEV1) occurred in 16 of 56 never-smokers (28.6%) and 4 of 34 smokers (11.8%). Multiple logistic regression analysis found pack-yr of smoking to be associated with decreased ozone responsiveness (odds ratio [OR] 0.87, p = 0.017). Age, gender, and methacholine responsiveness were not predictive of responder status. Fourteen smokers and 25 nonsmokers were subsequently exposed once to air and twice to ozone; smokers as well as nonsmokers were consistent in their subsequent responsiveness (or lack of responsiveness) to ozone. Healthy smokers have smaller decrements in lung function and fewer symptoms in response to ozone exposure than do nonsmokers.

Adolescent↗
PubMed1997

Role of cytokine-induced neutrophil chemoattractant (CINC) in ozone-induced airway inflammation and hyperresponsiveness.

Cytokine-induced neutrophil chemoattractant (CINC) is a rat chemokine with potent chemoattractant effects on neutrophils. We determined the involvement of CINC in ozone-induced airway neutrophilia and bronchial hyperresponsiveness (BHR) in the rat. We found a marked increase in lung CINC messenger RNA (mRNA) within 2 h after cessation of ozone exposure (1 ppm for 3 h), as measured by Northern blot analysis, whereas rats exposed to room air had no detectable CINC mRNA. Ozone exposure induced a significant neutrophilia in bronchoalveolar lavage fluid (BALF) at 24 h after exposure (air-exposed rats: 4.2 +/- 2.0 x 10(4), versus ozone-exposed rats: 16.1 +/- 3.7 x 10(4)); prior treatment with a goat anti-CINC antibody (1 mg, intravenously) suppressed the neutrophilia (3.1 +/- 0.9 x 10(4)). When administered intratracheally, the antibody (230 micrograms) partially inhibited the influx of neutrophils. The increase in bronchial responsiveness to acetylcholine observed after ozone exposure was not inhibited by the anti-CINC antibody. The anti-CINC antibody (1 mg, intravenously) also inhibited BALF neutrophilia induced by exposure to a higher concentration of ozone (3 ppm, 3 h), without an effect on BHR. CINC is an important chemokine causing ozone-induced neutrophil chemoattraction, but is not involved in the induction of ozone-induced BHR. The neutrophil is unlikely to contribute to BHR in this model.

Acetylcholine↗
PubMed1997

Airway inflammation in smokers and nonsmokers with varying responsiveness to ozone.

Exposure to ozone causes symptoms, changes in lung function, and airway inflammation. We studied whether individuals who differ in lung-function responsiveness to ozone, or in smoking status, also differ in susceptibility to airway inflammation. Healthy subjects were selected on the basis of responsiveness to a classifying exposure to 0.22 ppm ozone for 4 h with exercise (responders, with a decrease in FEV1 > 15%; and non-responders, with a decrease in FEV1 < 5%). Three groups were studied: nonsmoker-nonresponders (n = 12), nonsmoker-responders (n = 13), and smokers (n = 13, 11 nonresponders and two responders). Each subject underwent two exposures to ozone and one to air, separated by at least 3 wk; bronchoalveolar and nasal lavages were performed on three occasions: immediately (early) and 18 h (late) after ozone exposure, and either early or late after air exposure. Recovery of polymorphonuclear leukocytes (PMN) increased progressively in all groups, and by up to 6-fold late after ozone exposure. Interleukin-6 (IL-6) and IL-8 increased early (by up to 10-fold and up to 2-fold, respectively), and correlated with the late increase in PMN. Lymphocytes, mast cells, and eosinophils also increased late after exposure. We conclude that ozone-induced airway inflammation is independent of smoking status or airway responsiveness to ozone.

Adolescent↗
PubMed2000

No effect of inhaled budesonide on the response to inhaled ozone in normal subjects.

Inhalation of ozone in normal subjects causes a neutrophilic inflammatory response in the airways. Pretreatment with inhaled corticosteroids reduces the inflammatory response to inhaled ozone in dogs. We undertook a double-blind, randomized, placebo-controlled, crossover study to investigate the effects of 2 wk of treatment with inhaled budesonide 800 microg twice daily or placebo prior to ozone exposure in humans. Fifteen (six male; mean age, 31.1 +/- 2.1 yr) healthy nonsmokers were exposed to 400 parts per billion (ppb) ozone for 2 h with intermittent exercise. Spirometry, exhaled carbon monoxide (CO) and nitric oxide (NO) levels, measurement of methacholine reactivity, and collection of exhaled air condensate and induced sputum samples were performed at baseline, preexposure, and at intervals up to 24 h postexposure. Ozone exposure led to significant decreases in spirometry and increased methacholine reactivity and sputum neutrophils and myeloperoxidase (MPO). There were no changes in exhaled NO and CO levels, or exhaled breath nitrite after ozone exposure. There were no differences in any of the parameters after treatment with budesonide compared with placebo, and no differences in the response to ozone between treatment groups. We conclude that a high dose of inhaled corticosteroid does not protect against the effects of ozone exposure in normal subjects.

Administration, Inhalation↗
PubMed1989

Exposure to low levels of ozone results in enhanced pulmonary retention of inhaled asbestos fibers.

Health effects associated with exposure to ozone at environmentally relevant concentrations are subject to considerable controversy. Currently, no compelling evidence exists that exposure to low levels of ozone leads to lasting impairment of pulmonary structure or function. One adverse health effect of ozone may be to change lung uptake or clearance functions for other inhaled air pollutants. As a test of this hypothesis, Fischer 344 rats were continuously exposed to 0.06 ppm ozone 7 days a week with a slow rise in ozone to a peak of 0.25 ppm and subsequent decrease to 0.06 ppm over a 9-h period five times each week for 6 wk. Three days after the end of ozone exposure, animals-were exposed to aerosolized asbestos fibers for 5 h and examined immediately after or 30 days after exposure to asbestos. Filtered air control animals were simultaneously exposed to asbestos. Immediately after the end of fiber exposure, lung asbestos fiber burden was similar in both groups. However, 1 month after exposure, fiber mass and fiber number were significantly greater (p less than 0.05) in the lungs of animals exposed to ozone than in the lungs of those exposed to air. These findings suggest that ambient levels of ozone can impair clearance of fibrogenic and carcinogenic materials such as asbestos from the lungs and represent an important adverse effect of prolonged exposure to low levels of this oxidant gas.

Animals↗
PubMed1991

The effect of antioxidants on ozone-induced airway hyperresponsiveness in dogs.

The role of oxygen radicals in causing ozone-induced airway hyperresponsiveness in dogs was examined by pretreating dogs with allopurinol and/or deferoxamine mesylate (desferal), which are inhibitors of oxygen radical generation, before ozone inhalation. Acetylcholine airway responsiveness was measured before and after either air or ozone inhalation (3 ppm for 20 min) on 5 experimental days separated by at least 2 wk. On each day, the dogs were pretreated intravenously with allopurinol (50 mg/kg) followed by inhaled desferal (1,000 mg inhalation) or with allopurinol followed by the diluent for desferal or with the diluent for allopurinol and desferal or with both diluents. The effect of ozone on acetylcholine airway responsiveness was expressed as the differences in the log-transformed preozone-postozone acetylcholine provocative concentrations. When dogs received both diluents or either treatment alone, ozone inhalation caused airway hyperresponsiveness. The mean log differences for the preozone-postozone acetylcholine provocative concentration were 0.804 (SEM, 0.17) for both diluents, 0.524 (SEM, 0.16) for allopurinol alone, and 0.407 (SEM, 0.22) for desferal alone. However, the combination of allopurinol and desferal significantly inhibited the development of ozone-induced airway hyperresponsiveness, the log difference being 0.195 (SEM, 0.11) (p less than 0.05), without inhibiting ozone-induced neutrophil influx into the airways. The results suggest that the production of oxygen radicals is important in the pathogenesis of ozone-induced airway hyperresponsiveness.

Acetylcholine↗
PubMed1992

Functional and morphologic changes caused by acute ozone exposure in the isolated and perfused rat lung.

Ozone has been shown to increase airway resistance and/or airway reactivity in vivo in animals and humans. Because of the complexities inherent in studying this phenomenon in whole animals, we developed a model of ozone-induced effects on airway physiology using the isolated perfused rat lung. Rat lungs were suspended in an airtight chamber and perfused via the pulmonary circulation with a modified Krebs-Henseleit buffer containing 4.5% bovine albumin. Ventilation of the lungs was achieved by generating a fluctuating negative pressure within the chamber (-2 to -7 cm H2O) at a rate of 60 breaths/min. The lungs were ventilated with humidified 95% air and 5% CO2 alone (control condition) or mixed with ozone at 1.0 or 2.0 ppm. Transpulmonary pressure, flow rate, and tidal volume were recorded at 0, 1, 2, and 3 hours, and pulmonary resistance (RL) and dynamic compliance (Cdyn) were calculated. There was no significant difference in lung weight/total body weight ratios between the three groups at the end of the 3-h period. RL increased and Cdyn decreased in a time- and dose-dependent manner with ozone exposure. The percent increase above baseline in RL +/- SEM at 3 h was 9.4 +/- 4.1% for control lungs, 21.0 +/- 3.2% for 1.0 ppm ozone-exposed lungs, and 63.6 +/- 13.5% for 2.0 ppm ozone-exposed lungs. The percent decrease below baseline in Cdyn +/- SEM at 3 h was 27.4 +/- 2.1% for control lungs, 37.1 +/- 2.7% for 1.0 ppm ozone-exposed lungs, and 55.2 +/- 7.3% for 2.0 ppm ozone-exposed lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1995

CD4+ T lymphocyte modulation of ozone-induced murine pulmonary inflammation.

Inhalation of elevated levels of ozone produces a potent inflammatory response in the lung. The magnitude of this response to ozone exposure in mice is inbred strain dependent with the susceptible phenotype being exemplified by the C57BL/6J (B6) strain and the resistant phenotype by the C3H/HeJ (C3) strain. To examine the role of T lymphocytes in the regulation of ozone-induced pulmonary inflammation, mice were pretreated by an intraperitoneal injection of anti-Thy1.2 monoclonal antibody (mAb), anti-CD4+ mAb, or isotype-matched control antibodies (0.5 mg each) and subsequently exposed for 72 h to either filtered air or ozone (0.3 ppm). Immediately after ozone exposure, the cellular profile in the bronchoalveolar lavage fluids (BALF) was assessed. In isotype-treated controls of both strains of mice, ozone exposure induced significant increases in the numbers of macrophages, neutrophils, lymphocytes, and epithelial cells recovered in the BALF; however, the magnitude of each cell type recovered was significantly greater in B6 mice as compared with C3 mice. Both anti-Thy1.2 and anti-CD4+ monoclonal antibody treatments decreased the number of each cell type recovered in the B6 mice and increased the number of cells in the C3 mice. To determine if the CD4+ T-cell-derived cytokine interleukin (IL)-4 was involved in the differential effect of T-cell depletion on the ozone-induced inflammatory responses of C3 and B6 mice, mice were pretreated with either 400 ng of recombinant mouse IL-4 or vehicle, or 5.0 mg anti-IL-4 receptor monoclonal antibody or an isotype-matched antibody before either air or ozone exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Ozone-induced alterations in glutathione in lung subcompartments of rats and monkeys.

The current studies were designed to test two hypotheses: (1) differences in steady-state reduced glutathione levels are responsible for subcompartment differences in susceptibility to acute ozone injury, and (2) elevation of reduced glutathione concentrations accounts for the tolerance to further injury produced by repeated ozone exposure. Glutathione was measured in well-defined subcompartments of the lung of both rats and monkeys to compare alterations occurring in both target (distal trachea and terminal bronchiole) and nontarget areas (lobar bronchus, major daughter, minor daughter bronchus, and parenchyma) of the lung in species that differ in sensitivity to ozone exposure (rat is less susceptible than monkey). Glutathione concentrations were decreased in trachea of rats exposed to 0.4 ppm ozone for 2 h and increased in lobar bronchus and distal bronchiole after 2 h exposure at 1 ppm. In monkey, glutathione levels in most subcompartments were not altered by either 0.4 or 1.0 ppm ozone exposure for 2 h. The exceptions were the major daughter subcompartment (200% of control at 0.4 ppm exposure) and the distal bronchiole (55% of control at 1 ppm exposure). Ninety day ozone exposures (6 h/day x 5 days/week) in rats produced an elevation in glutathione (164% of control value) only in distal bronchiole at the 1 ppm exposure level. In a similar manner, glutathione levels in the distal bronchiole of monkeys exposed for 90 days to 1 ppm O3 were 165% of the corresponding control values. These results suggest the following: glutathione levels in target and nontarget areas of the lung and in susceptible versus less susceptible species are not the primary determinant in the differences observed in ozone toxicity; the response of lung subcompartments to short-term ozone exposure varied depending on airway subcompartment and species; increased glutathione levels may be one reason for adaptation of some airway epithelial cells from rats and monkeys exposed to O3 for long periods; and use of well-defined segments of the lung provides a means of assessing changes in target areas of the lung without dilution from nontarget areas.

Animals↗
PubMed1997

Mucous cell metaplasia in rat nasal epithelium after a 20-month exposure to ozone: a morphometric study of epithelial differentiation.

The present study was designed to examine the effects of long-term ozone exposure on nasal epithelia and intraepithelial mucosubstances (IM) throughout the nasal airways of F344/N rats. Animals were exposed to 0 (controls), 0.12, 0.5, or 1.0 ppm ozone, 6 h/day, 5 days/wk, for 20 mo. Rats were killed 1 wk after the end of the exposure, and nasal tissues were processed for light and electron microscopy. Standard morphometric techniques were used to determine epithelial cell densities and the amounts of IM in the surface epithelium lining the nasal airways. No mucous cells or IM were present in the epithelia lining the nasal lateral meatus and maxillary sinus of rats exposed to 0 or 0.12 ppm ozone. In contrast, rats exposed to 0.5 or 1.0 ppm ozone had marked mucous cell metaplasia (MCM) with numerous mucous cells and conspicuous amounts of IM in the surface epithelium lining these upper airways. Ozone-induced increases in total epithelial cells (i.e., epithelial hyperplasia) were present only in rats exposed to 1.0 ppm. The results of this study indicate that rats chronically exposed to 1.0 or 0.5 ppm, but not 0.12 ppm, ozone can develop marked MCM with significant increases in IM in both proximal and distal nasal airways. The epithelial changes observed throughout the nasal passages of ozone-exposed rats may be adaptive responses in an attempt to protect the upper and lower respiratory tract from further ozone-induced injury.

Animals↗
PubMed2002

Deficiency in inducible nitric oxide synthase protects mice from ozone-induced lung inflammation and tissue injury.

Inhalation of ozone causes Type I epithelial cell necrosis and Type II cell hyperplasia and proliferation. This is associated with an accumulation of activated macrophages in the lower lung, which we have demonstrated contribute to tissue injury. Nitric oxide (NO) is a highly reactive cytotoxic macrophage-derived mediator that has been implicated in lung damage. In the present studies we used knockout mice with a targeted disruption of the gene for inducible nitric oxide synthase (NOSII) to analyze the role of NO in ozone-induced lung inflammation and tissue injury. Treatment of wild-type control mice with ozone (0.8 ppm) for 3 h resulted in a time-dependent increase in protein and cells in bronchoalveolar lavage fluid, which reached a maximum 24-48 h after exposure. Alveolar macrophages isolated from animals treated with ozone were found to produce increased amounts of NO, as well as peroxynitrite. This was correlated with induction of NOSII protein and nitrotyrosine staining of lung macrophages in tissue sections and in culture. Production of superoxide anion and prostaglandin (PG)E2 by alveolar macrophages was also increased after ozone inhalation. In contrast, alveolar macrophages from NOSII knockout mice did not produce reactive nitrogen intermediates even after ozone inhalation. Moreover, production of PGE2 was at control levels. NOSII knockout mice were also protected from ozone-induced inflammation and tissue injury, as measured by bronchoalveolar lavage protein and cell number. There was also no evidence of peroxynitrite-mediated lung damage in these animals. Taken together, these data demonstrate that NO, produced via NOSII, and potentially, its reactive oxidative product peroxynitrite, play a critical role in ozone-induced release of inflammatory mediators and in tissue injury.

Administration, Inhalation↗
PubMed2003

Superoxide dismutase-overexpressing mice are resistant to ozone-induced tissue injury and increases in nitric oxide and tumor necrosis factor-alpha.

Reactive oxygen intermediates have been implicated in lung injury induced by inhaled irritants. The present studies used mice overexpressing Cu/Zn-superoxide dismutase (SOD+/+) to analyze their role in ozone-induced lung inflammation and cytotoxicity. Treatment of wild-type mice with ozone (0.8 ppm, 3 h) resulted in increased bronchoalveolar lavage fluid protein, which was maximal after 24-48 h. Significant increases in lung macrophages and 4-hydroxyalkenals were also observed. In contrast, bronchoalveolar lavage fluid protein and macrophage content and 4-hydroxyalkenals were at control levels in ozone-treated SOD+/+ mice. There was also no evidence of peroxynitrite-mediated lung damage, demonstrating that SOD+/+ mice are resistant to ozone toxicity. Whereas alveolar macrophages from wild-type mice produced increased amounts of nitric oxide and expressed more inducible nitric oxide synthase, phospholipase A(2), and tumor necrosis factor-alpha after ozone inhalation, this was not evident in cells from SOD+/+ mice. Ozone-induced decreases in interleukin-10 were also not observed. In wild-type mice, ozone inhalation resulted in activation of nuclear factor-kappaB, which regulates proinflammatory gene activity. This response was significantly reduced in SOD+/+ mice. These data demonstrate that antioxidant enzymes play a critical role in ozone-induced tissue injury and in inflammatory mediator production.

Administration, Inhalation↗
PubMed2006

Prolonged ozone exposure in an allergic airway disease model: adaptation of airway responsiveness and airway remodeling.

BACKGROUND: Short-term exposure to high concentrations of ozone has been shown to increase airway hyper-responsiveness (AHR). Because the changes in AHR and airway inflammation and structure after chronic ozone exposure need to be determined, the goal of this study was to investigate these effects in a murine model of allergic airway disease. METHODS: We exposed BALB/c mice to 2 ppm ozone for 4, 8, and 12 weeks. We measured the enhanced pause (Penh) to methacholine and performed cell differentials in bronchoalveolar lavage fluid. We quantified the levels of IL-4 and IFN-gamma in the supernatants of the bronchoalveolar lavage fluids using enzyme immunoassays, and examined the airway architecture under light and electron microscopy. RESULTS: The groups exposed to ozone for 4, 8, and 12 weeks demonstrated decreased Penh at methacholine concentrations of 12.5, 25, and 50 mg/ml, with a dose-response curve to the right of that for the filtered-air group. Neutrophils and eosinophils increased in the group exposed to ozone for 4 weeks compared to those in the filtered-air group. The ratio of IL-4 to INF-gamma increased significantly after exposure to ozone for 8 and 12 weeks compared to the ratio for the filtered-air group. The numbers of goblet cells, myofibroblasts, and smooth muscle cells showed time-dependent increases in lung tissue sections from the groups exposed to ozone for 4, 8, and 12 weeks. CONCLUSION: These findings demonstrate that the increase in AHR associated with the allergic airway does not persist during chronic ozone exposure, indicating that airway remodeling and adaptation following repeated exposure to air pollutants can provide protection against AHR.

Adaptation, Physiological↗
PubMed1993

Introduction to working group on tropospheric ozone, Health Effects Institute environmental epidemiology planning project.

The working group on tropospheric ozone of the Health Effects Institute has evaluated the need for epidemiologic studies on the health effects of ozone (O3) exposure. This paper summarizes current data and identifies possible research questions. The extent to which ozone exposure results in chronic health effects is largely undefined and is the central issue for epidemiologic studies. Most current data focus on transient endpoints; the link between acute changes in symptoms and/or lung function and possible chronic effects has not been established. Concepts of ozone-induced health effects have been extended to include processes of chronic disease (e.g., markers of ongoing inflammation and repair, markers of accelerated lung aging). Traditional epidemiologic studies performed have focused only on accelerated lung aging and are limited by a number of methodologic problems. Recent, very preliminary, studies suggest new opportunities for the use of human lung tissue and a variety biological response markers as part of epidemiologic studies. The identification of sensitive subpopulations with regard to ozone-induced health effects has been studied incompletely and is important both in terms of study efficiency and mechanistic insight. Methodologic advances in the reconstruction of past ozone exposure are seen as essential, as is the incorporation of emerging markers of biologic response to ozone into traditional epidemiologic study designs. Finally, more data on the joint and independent contribution of other ambient air pollutants to putative ozone-induced health effects is warranted.

Environmental Exposure↗
PubMed1998

Increased nitric oxide synthase in the lung after ozone inhalation is associated with activation of NF-kappa B.

Acute inhalation of ozone is associated with a inflammatory response characterized by the accumulation of macrophages at sites of tissue injury. These cells, along with resident alveolar epithelial cells, become activated and release cytotoxic and proinflammatory mediators, such as nitric oxide (.NO), that we speculate contribute to toxicity. In these studies we analyzed mechanisms regulating increased .NO synthase activity in lung macrophages and type II cells after ozone inhalation. Brief exposure of rats to ozone (2 ppm for 3 hr) resulted in an increase in .NO production by alveolar macrophages as well as type II cells in response to the inflammatory mediators lipopolysaccharide and interferon gamma. These effects were apparently due to increased expression of inducible .NO synthase (iNOS) protein and mRNA, which were evident in vitro and in situ in histologic sections. .NO production and iNOS protein expression by both macrophages and epithelial cells were blocked by pyrrolidine dithiocarbamate (PDTC), an agent that inhibits activity of nuclear transcription factor kappa B (NF-kappa B). Cells from ozone-treated animals were less sensitive to the effects of PDTC than cells from control animals. Using electrophoretic mobility shift assays, we measured NF-kappa B binding activity in nuclear extracts of cells from control and ozone-exposed animals. Treatment of rats with ozone resulted in a time-dependent increase in NF-kappa B binding activity in both cell types, reaching a maximum in cells isolated 12 to 24 hr after ozone inhalation. Taken together, these data suggest that changes in the activity of NF-kappa B signaling are important in the response of lung macrophages and type II epithelial cells to cytokines after ozone inhalation.

Animals↗