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Ozone-induced Inflammation Is Attenuated with Multiday Exposure
Abstract
It is well known that ozone (O3) causes acute lung inflammation. What is not known is whether there is progression of the inflammatory response in humans with repeated short-term exposures. Our study was designed to test the hypothesis that repeated exposures to a high-ambient concentration of O3 (0.2 ppm) over several days would cause more inflammation than a single exposure. Fifteen healthy volunteers were exposed in random fashion to 0.2 ppm ozone for 4 h on a single day and to 0.2 ppm O3 for 4 h on 4 consecutive days while exercising moderately for 30 min of each hour. Pulmonary function tests were obtained immediately before and after each 4-h exposure. Bronchoscopy was performed 20 h after the completion of each exposure arm to obtain bronchoalveolar lavage (BAL) for measurement of markers of inflammation. Our results show initial progression followed by attenuation of the acute physiologic response to O3 with repeated daily exposures. We found a significant difference in percent change in FEV1, FVC, and specific airway resistance (SRaw) across the single-day exposure when compared with the change across Day 4 of the 4-d exposure. Bronchial fraction (the first 15 ml of BAL return) and BAL were analyzed for the following end points: total and differential cell counts, total protein, lactate dehydrogenase (LDH), fibronectin, interleukin-6 (IL-6), interleukin-8 (IL-8), and granulocyte-macrophage colony-stimulating factor (GM-CSF). In the bronchial fraction the number of polymorphonuclear cells (PMN)s and fibronectin concentration were significantly decreased after 4-d exposure compared with single-day exposure. In BAL, significant decreases in the number of PMNs, fibronectin, and IL-6 were found after 4-d exposure versus single-day exposure. These results suggest that there is attenuation of the O3-induced inflammatory response in both proximal airways and distal lung with repeated daily exposures.
... The proinflammatory and inflammatory effects of acute O 3 exposure exhibit interindividual variability and are reproducible across exposures both in vivo and in vitro (Holz et al., 1999;Bowers et al., 2018). Additionally, in vivo controlled human exposure studies have demonstrated that the effects of single and repeated exposures differ in that airway proinflammation and inflammation resulting from acute O 3 exposure are attenuated following repeated exposures (Christian et al., 1998;Devlin et al., 1997). ...
... Rationale for O 3 dosing. When considered in the context of quantifying dose as the product of concentration and exposure time (ie, C Â T), the dose used in this study is comparable with in vivo human studies evaluating the effects of repeated O 3 exposure on proinflammatory endpoints (Christian et al., 1998;Devlin et al., 1997;Jö rres et al., 2000). The dose used here is also similar to, or less than, previously published in vitro (Bowers et al., 2018;Devlin et al., 1994;McCullough et al., 2014McCullough et al., , 2016Wang et al., 2018;Wu et al., 2011) and in vivo (Devlin et al., 1996;Hernandez et al., 2010;Koren et al., 1989) human acute exposure studies. ...
... Acute exposure to O 3 causes airway neutrophilia accompanied by increases in proinflammatory cytokines in the respiratory tract (Devlin et al., 1991;Kim et al., 2011;Koren et al., 1989); however, these effects are attenuated following 4-5 days of repeated exposures (Christian et al., 1998;Devlin et al., 1997). Bronchial epithelial cells upregulate prototypical proinflammatory (eg, IL-8 and IL-6) and oxidative stress-responsive genes (eg, HMOX1 and COX2) in response to acute O 3 exposures in vitro at both the transcript (McCullough et al., 2014(McCullough et al., , 2016Jaspers et al., 1997Jaspers et al., , 1998 and protein levels (Bayram et al., 2001;Devlin et al., 1994;Wu et al., 2011). ...
Inhaled chemical/material exposures are a ubiquitous part of daily life around the world. There is a need to evaluate potential adverse effects of both single and repeat exposures for thousands of chemicals and an exponentially larger number of exposure scenarios (e.g., repeated exposures). Meeting this challenge will require the development and use of in vitro new approach methodologies (NAMs); however, two major challenges face the deployment of NAMs in risk assessment are (1) characterizing what apical outcome(s) acute assays inform regarding the trajectory to long term events, especially under repeated exposure conditions, and (2) capturing inter-individual variability as it informs considerations of potentially susceptible and/or vulnerable populations. To address these questions, we used a primary human bronchial epithelial cell air-liquid interface model exposed to ozone (O3), a model oxidant and ubiquitous environmental chemical. Here we report that O3-induced pro-inflammatory gene induction is attenuated in repeated exposures thus demonstrating that single acute exposure outcomes do not reliably represent the trajectory of responses after repeated or chronic exposures. Further, we observed 10.1-, 10.3-, 14.2-, and 7-fold ranges of induction of IL-8, IL-6, HMOX1, and COX2 transcripts, respectively, within in our population of 25 unique donors. Calculation of sample size estimates that indicated that 27, 24, 299, and 13 donors would be required to significantly power similar in vitro studies to identify a two-fold change in IL-8, IL-6, HMOX1, and COX2 transcript induction, respectively, to inform considerations of the uncertainty factors to reflect variability within the human population (UFH) for in vitro studies.
... Whereas acute exposures to O 3 in humans and animals have been reported to cause inflammation and decrements in lung function, the inflammatory response is attenuated during multiday O 3 inhalation [10,11] partly due to increased antioxidant defense capacities [7,9,12,13] . Surprisingly, O 3 -induced biochemical and morphological changes in lung tissue do not show this attenuated response and may even progress with ongoing exposure [13]. ...
... It might appear that the concentration of O 3 used in the present study (0.5 ppm) was relatively high as compared to the level of that could be encountered on a day of high urban air pollution. Nevertheless, in several studies human subjects were exposed to O 3 levels close (0.2 -0.4 ppm) to the one used in the present study [10,55]. Interestingly, in the collaborative ozone project supported by the Health Effects Institute [1] it was shown that chronic exposure to O 3 below 0.5 ppm has no significant effect on lungs, including surface epithelium, mucus or inflammation. ...
... It is well known that short-term O 3 exposure causes lung inflammation [1,10,11] and no particular attention was paid in the present study to the inflammatory response to O 3 exposure. However, on the basis of an attenuation of O 3 -induced inflammation with intermittent O 3 exposure [10,11], we deliberately excluded examination of the inflammatory response. ...
Ozone (O3) is one of the molecular species most reactive to which are exposed living species. O3 acts primarily on the pulmonary system by undicucing oxidative stress. Because susceptibility to oxidative stress varies with age, we studied alterations of pulmonary balance between production of reactive oxygen species (ROS) and their elimination, in immature (21 days), adult (6 months) and old rats (20 months) during O3 exposure (0,5 ppm, 12 h/day for 7 days). For this purpose we have specifically studied pulmonary mitochondria as ROS source, main antioxidant enzyme activities, contents in stress protein (HSP72), 8-oxodGuo and DNA adducts resulting from lipid peroxidation. These works have shown that our protocol of O3 exposure did not induce lung oxidative stress in adult rats. We confirmed that immature and old rats were more sensitive during O3 challenge than adults. Indeed, O3 generates oxidative stress which leads to modification of ventilatory function and pulmonary DNA oxidation in these two populations. Parameters which take part in greatest susceptibility to O3 differ according to the age. We concluded that the mitochondria is not a major source of pulmonary ROS in our model of O3 exposure. Secondly, with the sights of anti-inflammatory properties of polyunsaturated fatty acids Ω3, we studied the effect of a Ω3 supplementation in immature and old rats exposed to O3. The supplementation in Ω3 limits the pulmonary DNA oxidation in immature and old rats. Paradoxically, in old rats this supplementation provokes an increase in lipid peroxidation susceptibility
... The first mechanism would result from the increase in the permeability of the lung epithelial barrier, and this has as a consequence a higher diffusion of CC16 into the blood. This can happen following exposure to ozone, which causes epithelial lung injury, or more specifically, damage to the tight junctions of the cells ( fig. 4) [51,53]. A second possibility is the decrease or increase in the production or secretion of CC16 from the Clara cells present in the respiratory tract. ...
... Unfortunately, several challenges are present for the development of research on chronic exposure to air pollution on a human exercising population. Christian et al. [53] showed an attenuation of the inflammatory response in BAL after four consecutive days of exposure to ozone. Nevertheless, it seems that, although neutrophil recruitment and IL-6 concentration in the respiratory tract is attenuated with multiday short-term exposures, airway epithelial injury may continue to occur. ...
... These data, thus, demonstrate that airway inflammation persists despite the attenuation of some inflammatory markers in BAL. It is important to point out that such persistent injury could lead to airway remodeling, which has been observed in several animal studies, but needs further investigation in humans [53]. ...
... 오존은 주로 호흡기에 의한 흡입과 눈 및 피부 등의 접 촉에 의해 노출되는데, 오존농도가 높아지면 눈과 목의 자극 증상을 느낄 수 있고, 기도 수축으로 인한 호흡곤 란, 기침, 두통, 및 오심, 등의 증세가 발생할 수 있다 1,5) . 급성 오존 노출의 경우, 염증반응으로 폐에서 중성구 (neutrophils), 단핵구(monocytes), 및 수지상 세포 (dendritic cells)가 증가하고 6,7) , 폐기능 장애가 유발될 수 있다 8) . 만성 오존 노출의 경우, 알레르기성 비염, 천명 의 유병율 및 항원 감작(allergen sensitization)이 증가 하고 9,10) , 오존의 농도가 증가함에 따라 호흡기 원인으로 인한 사망률도 증가한다는 보고가 있다 11) . ...
... 오존 노출농도 에 따른 급성 증상은 0.05~0. 2 14) 가 있다. 동물 및 세포실험연구에서는 오존 노출 후 젖 당 탈수소효소(lactate dehydrogenase)가 증가하였고 15,16) , 이는 세포의 손상으로 인해 증가한 것으로 여겨진 다. 인체에 대한 영향 연구로는 오존 노출에 의한 호흡기 증상 17) , 객담 및 기관지폐포세척검사 이상소견 7 Cough, Throat discomfort Coarse breath sound Mild erosions on N/S laryngeal mucosa *chest X-ray, � pulmonary function test, � non-specific. 참 고 문 헌 ...
... An additional issue worthy of consideration is how systemic inflammation may vary with consecutive daily exposures to elevated ozone concentrations. This was not addressed in this study, but whilst there is an extensive literature demonstrating attenuation of lung function decrements with multi-day ozone exposures [42], the available data on pulmonary inflammation is mixed, with evidence ranging from apparent attenuation [42], to persistence [43] as well as exacerbation [44]. It therefore remains unclear whether successive ozone challenge induces a chronic persistent inflammation, cycles of equivalent acute episodes, or the induction of tolerance and therefore the relationship between systemic and pulmonary inflammation under these conditions is currently unknown. ...
... An additional issue worthy of consideration is how systemic inflammation may vary with consecutive daily exposures to elevated ozone concentrations. This was not addressed in this study, but whilst there is an extensive literature demonstrating attenuation of lung function decrements with multi-day ozone exposures [42], the available data on pulmonary inflammation is mixed, with evidence ranging from apparent attenuation [42], to persistence [43] as well as exacerbation [44]. It therefore remains unclear whether successive ozone challenge induces a chronic persistent inflammation, cycles of equivalent acute episodes, or the induction of tolerance and therefore the relationship between systemic and pulmonary inflammation under these conditions is currently unknown. ...
Ozone concentrations are predicted to increase over the next 50 years due to global warming and the increased release of precursor chemicals. It is therefore urgent that good, reliable biomarkers are available to quantify the toxicity of this pollutant gas at the population level. Such a biomarker would need to be easily performed, reproducible, economically viable, and reflective of ongoing pathological processes occurring within the lung.
We examined whether blood neutrophilia occurred following a controlled ozone challenge and addressed whether this could serve as a biomarker for ozone-induced airway inflammation. Three separate groups of healthy subjects were exposed to ozone (0.2 ppm, 2h) and filtered air (FA) on two separate occasions. Peripheral blood samples were collected and bronchoscopy with biopsy sampling and lavages was performed at 1.5h post exposures in group 1 (n=13), at 6h in group 2 (n=15) and at 18h in group 3 (n=15). Total and differential cell counts were assessed in blood, bronchial tissue and airway lavages.
In peripheral blood, we observed fewer neutrophils 1.5h after ozone compared with the parallel air exposure (-1.1±1.0x10(9) cells/L, p<0.01), at 6h neutrophil numbers were increased compared to FA (+1.2±1.3x10(9) cells/L, p<0.01), and at 18h this response had fully attenuated. Ozone induced a peak in neutrophil numbers at 6h post exposure in all compartments examined, with a positive correlation between the response in blood and bronchial biopsies.
These data demonstrate a systemic neutrophilia in healthy subjects following an acute ozone exposure, which mirrors the inflammatory response in the lung mucosa and lumen. This relationship suggests that blood neutrophilia could be used as a relatively simple functional biomarker for the effect of ozone on the lung.
... A number of clinical studies have focused on multiday exposure (100-800 µg m Ϫ3 ) to ozone (Hackney et al., 1977;Farrel et al., 1979;Folinsbee et al., 1980Folinsbee et al., , 1994Horvath et al., 1981;Bedi et al., 1989;Folinsbee and Hazucha, 1989;Devlin et al., 1997;Christian et al., 1998). In general, these studies show that during repeated daily exposures to ozone, lung function decrement increases after the first exposures, followed by decrease on subsequent exposures. ...
... In the second stage, from the third day on, decrease in the initial response occurs, involving progressive diminution and finally complete disappearance of the effects. Decrease of respiratory symptoms (Folinsbee et al., 1994) and indicators of inflammation in BAL fluid (Devlin et al., 1997;Christian et al., 1998) were also found. ...
Exposure to ambient ozone can result in lung function decrement in humans. Clinical studies in which humans were repeatedly exposed to ozone have revealed that lung function decrement decreases after each additional exposure event. Ozone concentrations in the ambient atmosphere show strong seasonal, episodic, and diurnal fluctuations. Accordingly, in quantitative risk analysis a model is needed, which accounts for the time dependence of the lung function decrement on observed exposure patterns. This paper presents a toxico-dynamic model predicting lung function and cellular injury and repair over time. Any ozone exposure pattern can be used as an input to the model, to predict the development of lung function decrement in time. The model incorporates the biological mechanisms generally believed to play a role in the lung function decrement due to ozone exposure. A comparison was made of the model’s predictions and observed lung function decrements in seven different clinical studies. This type of ozone effect modelling and its further progress may contribute to risk evaluation and assessment of ambient exposures.
... Ozone can also cause indirect oxidation by stimulating the epithelial cells to release a variety of pro-inflammatory mediators and more reactive oxygen species (Pryor et al., 1995). As a result, if the oxidative stress is sufficient it will activate an inflammatory response which may lead to an increase in airway neutrophilia and lung injury (Christian et al., 1998;Stenfors et al., 2002). ...
... These increases were only statistically significant with placebo ingestion. As previously explained, ozone can cause lung epithelial injury (Christian et al., 1998); therefore, it is possible that the higher antioxidant concentration in the airways of the runners after the supplementation might have provided protection against the damaging oxidative effects on epithelial cells of the ozone gas. Besides being a sensitive marker of lung epithelial integrity , CC16 is also thought to play an important role in decreasing the inflammation of the respiratory tract and protecting it against inhaled particles, such as pollutants (Robin et al., 2002) and chloramines (Romberg et al., 2011). ...
In this study, the effect of vitamin C and E supplementation on lung injury and performance of runners were analyzed. Using a randomized, double-blinded, crossover design, nine runners participated in two experimental trials: a 2-week Vitamin trial (vitamin C = 500 mg/day + vitamin E = 100 IU/day) and a 2-week Placebo trial. At the end of each supplementation period the runners performed an 8-km time-trial run in a hot (31°C), humid (70% rh), and ozone-polluted (0.10 ppm O(3)) environmental chamber. Nasal lavage and blood samples were collected pre-, post-, and 6-h post-exercise to assess antioxidant status and CC16 as lung injury marker. Higher plasma (pre- and post-exercise) and nasal lavage (post-exercise) antioxidant concentration were found for the Vitamin trial. Nevertheless, this did not result in performance differences (Vitamin trial: 31:05 min; Placebo trial: 31:54 min; P = 0.075) even though significant positive correlations were found between antioxidant concentration and improvement in time to complete the run. CC16 was higher post-exercise in the Placebo trial (P < 0.01) in both plasma and nasal lavage. These findings suggest that antioxidant supplementation might help to decrease the lung injury response of runners when exercising in adverse conditions, but has little effect on performance.
... Exposure to ozone has also been linked to lung epithelial injury (Christian et al. 1998) resulting in an increase in the lung epithelial barrier permeability. For the assessment of lung injury and toxicity, Clara cell protein (CC16) has been shown to be a sensitive and suitable biomarker (Hermans and Bernard 1999;Blomberg et al. 2003;McAuley and Matthay 2009). ...
... The assessment of CC16 serum levels can also be used as a specific biomarker of the airway epithelium integrity. If there is an increase in the permeability of the lung epithelial barrier, which can happen following exposure to ozone (Christian et al. 1998), there may be an increased diffusion rate of CC16 to the blood . Nevertheless, in the present study no alterations in plasma CC16 were observed. ...
To investigate the acute effect of a hot, humid and ozone-polluted (O(3)) environment on lung inflammation and oxidative tress of runners performing 8 km time trial run. Using a single-blinded randomized design, 10 male athletes (mean[Formula: see text]= 64.4 mlO(2) kg(-1) min(-1), SD = 4.4) took part in a time trial run in four different environmental conditions: 20°C + 50% relative humidity (rh) (Control); 20°C + 50% rh + 0.10 ppm O(3) (Control + O(3)); 31°C + 70% rh (Heat); 31°C + 70% rh + 0.10 ppm O(3) (Heat + O(3)). Blood samples and nasal lavage were collected post-exercise and analyzed for inflammatory, epithelial damage and oxidative stress markers. Data were analyzed using repeated measures ANOVA with Tukey's post hoc test. A significant increase in CC16 concentration (P < 0.05) and GSH/protein concentration (P < 0.05) in the upper respiratory airways was observed following the 8 km run in the Heat + O(3) trial compared with the control trial. There were no differences in the neutrophil counts between trials. No differences were observed for the other antioxidants analyzed. A hot, humid and ozone-polluted environment (0.1 ppm) elicits an early epithelial damage and antioxidant protection process in the upper respiratory airways of athletes immediately after performing 8 km time trial run.
... Previous epidemiological and experimental studies have found that O3 exposure may cause systemic inflammation (Arjomandi et al., 2018;Christian et al., 1998;Mirowsky et al., 2017;Pirozzi et al., 2015), oxidative stress damage (Day et al., 2017;Jantzen et al., 2018;Paffett et al., 2015) or neuronal response (Chounlamountry et al., 2015;Gackiere et al., 2011;Martinez-Lazcano et al., 2013), which can cause cardiometabolic disorders, such as hyperlipidemia (Kim et al., 2019;Miller et al., 2016a) and abnormal glucose metabolism (Chuang et al., 2010;Chuang et al., 2011). Specifically, studies have found that O3 does induce insulin resistance and oxidative stress, as well as endoplasmic reticulum stress (Vella et al., 2015). ...
... Previous epidemiological and experimental studies have found that O3 exposure may cause systemic inflammation (Arjomandi et al., 2018;Christian et al., 1998;Mirowsky et al., 2017;Pirozzi et al., 2015), oxidative stress damage (Day et al., 2017;Jantzen et al., 2018;Paffett et al., 2015) or neuronal response (Chounlamountry et al., 2015;Gackiere et al., 2011;Martinez-Lazcano et al., 2013), which can cause cardiometabolic disorders, such as hyperlipidemia (Kim et al., 2019;Miller et al., 2016a) and abnormal glucose metabolism (Chuang et al., 2010;Chuang et al., 2011). Specifically, studies have found that O3 does induce insulin resistance and oxidative stress, as well as endoplasmic reticulum stress (Vella et al., 2015). ...
Objective
To investigate potential effects of short- and medium-term exposure to low levels of ozone (O3) on glucose-homeostasis in non-diabetic older adults.
Methods
166 non-diabetic, older participants in Beijing were deemed eligible to partake in this longitudinal population-based study. Observations were recorded on three separate occasions from November 2016 up until January 2018. Concentrations of outdoor O3 were monitored throughout the study period. Biomarkers indicative of glucose-homeostasis, including fasting blood glucose, insulin, HbAlc, glycated albumin percentage (glycated albumin/albumin), HOMA-IR and HOMA-B were measured at 3 sessions. A linear mixed effects model with random effects was adopted to quantify the effect of O3 across a comprehensive set of glucose-homeostasis markers.
Results
Short-term O3 exposure positively associated with increased fasting blood glucose, insulin, HOMA-IR and HOMA-B. The effect on glucose occurred at 3-, 5-, 6- and 7-days, although the largest effect manifested on 6-days (5.6%, 95% CI: 1.4, 9.9). Significant associations with both insulin and HOMA-IR were observed on the 3- and 4-days. For HOMA-B, positive associations were identified from 3- to 7-days with estimates ranging from 40.0% (95% CI: 2.3, 91.5) to 83.1% (95% CI: 25.3, 167.5). Stratification suggests that women may be more susceptible to short-term O3 exposure. There does not appear to be a significant association between O3 and glucose-homeostasis in medium-term exposures.
Conclusions
In this study, we found that O3 exposure is at least partially associated with type II diabetes in older adults with no prior history of this condition. O3 therefore appears to be a potential risk factor, which is a particular concern when we consider the rise in global concentrations. Evidence also suggests that women may be more susceptible to short-term O3 exposure although we are not quite sure why. Future research may look to investigate this phenomenon further.
... 89 In the lower airways, an early neutrophilic, macrophages, and monocytic inflammation followed exposure of healthy volunteers to ozone. 90 These data highlight the ability of ambient particulates to elicit an antigenindependent allergic inflammation. ...
Allergic rhinitis affects the quality of life of millions of people worldwide. Air pollution not only causes morbidity, but nearly 3 million people per year die from unhealthy indoor air exposure. Furthermore, allergic rhinitis and air pollution interact. This report summarizes the discussion of an International Expert Consensus on the management of allergic rhinitis aggravated by air pollution. The report begins with a review of indoor and outdoor air pollutants followed by epidemiologic evidence showing the impact of air pollution and climate change on the upper airway and allergic rhinitis. Mechanisms, particularly oxidative stress, potentially explaining the interactions between air pollution and allergic rhinitis are discussed. Treatment for the management of allergic rhinitis aggravated by air pollution primarily involves treating allergic rhinitis by guidelines and reducing exposure to pollutants. Fexofenadine a non-sedating oral antihistamine improves AR symptoms aggravated by air pollution. However, more efficacy studies on other pharmacological therapy of coexisting AR and air pollution are currently lacking.
... Fourth, in reality, air pollution is dynamic and subject to migrations across local boundaries [101,102]. ...
Urban development can have negative impacts on the environment through various mechanisms. While many air quality studies have been carried out in more developed nations, Eastern Caribbean (EC) countries remain understudied. This study aims to estimate the concentrations of air pollutants in the EC nation of St. Kitts and Nevis. Transport, recreation and construction sites were selected randomly using local land use records. Pollutant levels were measured repeatedly for numerous 1-hour intervals in each location between October 2015 and November 2018. Weather trends and land use characteristics were collected concurrent to sampling. Across 27 sites, mean NO 2 , O 3 , SO 2 , PM 10 and PM 2.5 levels were 26.61 ppb (range: 0–306 ppb), 11.94 ppb (0–230 ppb), 27.9 ppb (0–700 ppb), 52.9 μ g m ⁻³ (0–10,400 μ g m ⁻³ ) and 29.8 μ g m ⁻³ (0–1556 μ g m ⁻³ ), respectively. Pollutants were elevated in high urban areas and generally significantly positively correlated with each other, with the exception of PM 10 . NO 2 levels in construction areas were generally comparable to those in transportation areas and higher than in recreation areas. O 3 levels were lower in construction than recreation and transport areas. SO 2 concentrations were lower in construction and recreation compared to transport sites. Construction and recreation PM 10 levels exceeded transport sites, while PM 2.5 was highest in construction areas. Additional bivariate and multivariate analysis were conducted to assess whether various meteorological, temporal and land use factors including rain, tour season and urban features explained variability in air pollutant concentrations. Tourist season and specific months, more than any other factors, contributed most to variability in pollutant concentrations. These new measurements of air pollution concentrations in an understudied nation may have important implications for health outcomes among exposed EC residents, and provide critical data for future exposure and epidemiologic research and environmental policy.
... Epidemiological [1,2] and experimental human studies [3] have shown that short-term ozone exposure may be associated with adverse health effects on the respiratory tract in the form of inflammation [4] and airflow obstruction [5]. The inflammation appears to intensify with repeated exposure [6]. Volume 2, Issue 1, Article ID: 100006 The degree of bronchoconstriction is determined by the O3 concentration, duration of exposure and the level of physical activity of the exposed person [7]. ...
Introduction
Ozone-generating UV-lamps are used to remove unwanted grease from ventilation systems. Irritant asthma after exposure to artificially produced ozone has been described at a Norwegian fish hatchery and a sewage plant, as well as in the Swedish paper industry.
We present cases that developed asthma after an accident with ozone-producing UV-systems in a restaurant kitchen.
Methods
Case series
Seven subjects that developed asthma were studied in relation to exposure, symptoms, medical history and clinical findings including lung function measurements, reversibility of airflow limitation and bronchial hyper responsiveness (BHR) to methacholine, both shortly after the accidental exposure and two years after the incident.
Result
Out of a total number of 127 possibly ozone-exposed employees, 55 employees reported symptoms, and seven employees were diagnosed with occupational asthma after the incident. Six of these seven subjects had either positive reversibility and/or positive BHR tests. Two years after cessation of exposure all seven subjects still needed treatment for asthma.
Three of the subjects had BHR despite the use of inhaled corticosteroids, all graded as ‘very mild BHR’. FVC, FEV1, FEV1/FVC ratio and FeNO values were within normal range in all cases. None had long absence from work or needed emergency treatment in hospital for their asthma.
Discussion
The adverse impact of ozone exposure on the airways is well known from epidemiological studies, where the focus has been on the negative health effects of ozone (O3) in ambient air, especially in large cities. Commercial use of the ozone gas’ odour absorbing and germ-killing properties has become more common in the last decade. Accidents involving ozone gas from air purifiers with UV-lamps may cause acute irritant asthma. There is a need for greater awareness in the use of ozone-generating devices.
... Results showed attenuation of lung function responses and some, but not all, markers of inflammation and injury; furthermore, mucosal biopsy results suggested morphological changes that did not diminish over time. However, in contrast, Christian et al. (1998) reported attenuation of the inflammatory response to ozone over 4 consecutive days of exposure to 200 ppb, as evidenced by reductions in polymorphonuclear luekocytes (PMNs), fibronectin, and interleukin-6 after repeated exposure versus a 1-day exposure. Toxicological studies also generally report attenuation of inflammatory responses. ...
A wealth of literature exists regarding the pulmonary effects of ozone, a photochemical pollutant produced by the reaction of nitrogen oxide and volatile organic precursors in the presence of sunlight. This paper focuses on epidemiological panel studies and human clinical studies of ozone exposure, and discusses issues specific to this pollutant that may influence study design and interpretation as well as other, broader considerations relevant to ozone-health research. The issues are discussed using examples drawn from the wider literature. The recent panel and clinical literature is also reviewed. Health outcomes considered include lung function, symptoms, and pulmonary inflammation. Issues discussed include adversity, reversibility, adaptation, variability in ozone exposure metric used and health outcomes evaluated, co-pollutants in panel studies, influence of temperature in panel studies, and multiple comparisons. Improvements in and standardization of panel study approaches are recommended to facilitate comparisons between studies as well as meta-analyses. Additional clinical studies at or near the current National Ambient Air Quality Standard (NAAQS) of 70 ppb are recommended, as are clinical studies in sensitive subpopulations such as asthmatics.
IMPLICATIONS
The pulmonary health impacts of ozone exposure have been well-documented using both epidemiological and chamber study designs. However, there are a number of specific methodological and related issues that should be considered when interpreting the results of these studies and planning additional research, including the standardization of exposure and health metrics to facilitate comparisons among studies.
... The application of these treatments has been already investigated both for egg industry [9][10][11] and for egg production farms [12]. It has been proven that a concentration of ozone of at least 1 ppm, is necessary to perform an effective bactericidal procedure but, in the same time, its toxicity has been demonstrated both for animals and humans [13,14]. Therefore, to evaluate and use these treatments in a real farming system, it is mandatory to avoid that hens and workers be exposed to this chemical element [14]. ...
In Italy, organic egg production farms use free-range housing systems with a big outdoor area and a flock of no more than 500 hens. With additional devices and/or farming procedures, the whole flock could be forced to stay in the outdoor area for a limited time of the day. As a consequence, ozone treatments of housing areas could be performed in order to reduce the levels of atmospheric ammonia and bacterial load without risks, due by its toxicity, both for hens and workers. However, an automatic monitoring system, and a sensor able to detect the presence of animals, would be necessary. For this purpose, a first sensor was developed but some limits, related to the time necessary to detect a hen, were observed. In this study, significant improvements, for this sensor, are proposed. They were reached by an image pattern recognition technique that was applied to thermografic images acquired from the housing system. An experimental group of seven laying hens was selected for the tests, carried out for three weeks. The first week was used to setup the sensor. Different templates, to use for the pattern recognition, were studied and different floor temperature shifts were investigated. At the end of these evaluations, a template of elliptical shape, and sizes of 135 × 63 pixels, was chosen. Furthermore, a temperature shift of one degree was selected to calculate, for each image, a color background threshold to apply in the following field tests. Obtained results showed an improvement of the sensor detection accuracy that reached values of sensitivity and specificity of 95.1% and 98.7%. In addition, the range of time necessary to detect a hen, or classify a case, was reduced at two seconds. This result could allow the sensor to control a bigger area of the housing system. Thus, the resulting monitoring system could allow to perform the sanitary treatments without risks both for animals and humans.
... Its full effectiveness is not proved yet, and some possible issues regarding production and health-of both animals and human operators-are under evaluation. In detail, it is well known that for a bactericidal purpose, a level of ozone (in the range of 1 ppm and above) is required [14], but on the other hand, the toxicity of ozone is dose-responsive and depends on the level and time of exposition, for both animals and humans [15,16]. ...
The development of a monitoring system to identify the presence of laying hens, in a closed room of a free-range commercial organic egg production farm, was the aim of this study. This monitoring system was based on the infrared (IR) technology and had, as final target, a possible reduction of atmospheric ammonia levels and bacterial load. Tests were carried out for three weeks and involved 7 ISA (Institut de Sélection Animale) brown laying hens. The first 5 days was used to set up the detection sensor, while the other 15 days were used to evaluate the accuracy of the resulting monitoring system, in terms of sensitivity and specificity. The setup procedure included the evaluation of different color background (CB) thresholds, used to discriminate the information contents of the thermographic images. At the end of this procedure, a CB threshold equal to an increase of 3 °C from the floor temperature was chosen, and a cutoff level of 196 colored pixels was identified as the threshold to use to classify a positive case. The results of field tests showed that the developed monitoring system reached a fine detection accuracy (sensitivity = 97.9% and specificity = 94.9%) and the IR technology proved to be a possible solution for the development of a detection sensor necessary to reach the scope of this study.
... The outcomes of O 3 exposure can be influenced by many factors [11], including the concentration of O 3 , the duration and type of exposure (acute or chronic), and the conditions of exposure (rest or exercise during exposure). Both in humans and in laboratory animals, the acute pulmonary effects of O 3 , including airway neutrophilia, lung hyperpermeability and decreased lung function are normally resolved within 2 days of recovery following exposure to normal air [12][13][14][15][16]. Controlled exposure studies of human volunteers and laboratory animals have shown that these responses may also be attenuated after short-term, repeated daily exposure to O 3 [17][18][19][20][21]. This phenomenon, referred to as tolerance or functional adaptation, is transient and may last for up to 2 weeks before full susceptibility to O 3 with acute pulmonary effects is restored again. ...
Background:
Ozone pollution has adverse effects on respiratory health in children and adults. This study was carried out in the mouse model to investigate the influence of age and to define the role of toll-like receptor four (TLR4) in the lung response to ozone exposure during postnatal development.
Methods:
Female mice (1 to 6 weeks of age) were exposed for 3 h to ozone (1 part per million) or filtered air. Analyses were carried out at six and 24 h after completion of exposure, to assess the effects on lung permeability, airway neutrophilia, expression of antioxidants and chemokines, and mucus production. The role of TLR4 was defined by examining TLR4 expression in the lung during development, and by investigating the response to ozone in tlr4-deficient mice.
Results:
Metallothionein-1, calcitonin gene-related product, and chemokine C-X-C ligand (CXCL) five were consistent markers induced by ozone throughout development. Compared with adults, neonates expressed lower levels of pulmonary TLR4 and responded with increased mucus production, and developed an attenuated response to ozone characterized by reduced albumin leakage and neutrophil influx into the airways, and lower expression of CXCL1 and CXCL2 chemokines. Examination of the responses in tlr4-deficient mice indicated that ozone-mediated airway neutrophilia, but not albumin leakage or mucus production were dependent on TLR4.
Conclusions:
Collectively, the data demonstrate that the response to ozone is determined by age and is partially dependent on TLR4 signaling. The reduced responsiveness of the neonatal lung to ozone may be due at least in part to insufficient pulmonary TLR4 expression.
... To minimize the potential for oxidative injury, the human lung has an integrated system of antioxidant enzymes and expendable soluble molecules. ROS may overwhelm the antioxidant system leading to a state of "oxidative stress," which is thought to contribute to the pathogenesis of a number of respiratory diseases [Christian et al., 1998, Hackney et al., 1977, Jorres et al., 2000. In addition, the inflammatory response of macrophages and neutrophils leads to production of more ROS [Grommes et al., 2011, Gwinn et al., 2006, Moraes et al., 2006. ...
Ozone is an important constituent of ambient air pollution and represents a major public health concern. Oxidative injury due to ozone inhalation causes the generation of reactive oxygen species and can be genotoxic. To determine whether ozone exposure causes genetic damage in peripheral blood lymphocytes, we used a well-validated cytokinesis-block micronucleus Cytome assay. Frequencies of micronuclei (MN) and nucleoplasmic bridges (NB) were used as indicators of cytogenetic damage. Samples were obtained from 22 non-smoking healthy subjects immediately before and 24-hr after controlled 4-hr exposures to filtered air, 100 ppb, and 200 ppb ozone while exercising in a repeated-measure study design. Inhalation of ozone at different exposure levels was associated with a significant dose-dependent increase in MN frequency (P < 0.0001) and in the number of cells with more than one MN per cell (P < 0.0005). Inhalation of ozone also caused an increase in the number of apoptotic cells (P = 0.002). Airway neutrophilia was associated with an increase in MN frequency (P = 0.033) independent of the direct effects of ozone exposure (P < 0.0001). We also observed significant increases in both MN and NB frequencies after exercise in filtered air, suggesting that physical activity is also an important inducer of oxidative stress. These results corroborate our previous findings that cytogenetic damage is associated with ozone exposure, and show that damage is dose-dependent. Further study of ozone-induced cytogenetic damage in airway epithelial cells could provide evidence for the role of oxidative injury in lung carcinogenesis, and help to address the potential public health implications of exposures to oxidant environments. Environ. Mol. Mutagen., 2014. © 2014 Wiley Periodicals, Inc.
Copyright © 2014 Wiley Periodicals, Inc.
... Numerosi articoli hanno ampiamente descritto gli effetti antinfiammatori 34 , antalgici 38 , antibatterici 20, [40][41][42]49,53,54,78,80 , virustatici 17,27,66,67 e il miglioramento perfusionale del microcircolo 59 , nonché la conseguente scomparsa del dolore ischemico, il recupero funzionale dei gruppi muscolo-articolari, la guarigione di ulcere trofiche 62,64 : tali effetti contribuiscono in modo significativo a migliorare la qualità della vita dei pazienti, a rendere più efficaci molte terapie farmacologiche 37 Il miglioramento perfusionale del microcircolo permette un'ottimizzazione nell'utilizzo dell'Ossigeno e del Glucosio 39 , stimola l'attivazione metabolica e lo smaltimento dei cataboliti, il cui accumulo contribuisce a determinare la noxa infiammatoria. Inoltre Amato 2 ha dimostrato che le proprietà emorreologiche 43,68,77 dell'Ozono sono maggiori di quelle della pentossifillina. ...
... Ved daglig moderat eksponering kan man opparbeide toleranse, slik at uendret eksponering gir mindre effekt etter om lag tre dager (2,3). Adaptasjonen kan vare i omtrent en uke (4,5). Ved moderat eksponering vil symptomene melde seg etter en til to timer (6, 7). ...
... Acute exposures, ranging from 80 to 200 ppb and lasting from 5 min to 6 h, induce an array of pulmonary responses, including reversible decrease in respiratory function, that can be observed within the first few hours after the start of the exposure and may persist for many hours or days after the exposure cessation (Lippmann and Schlesinger 2000). Chronic health effects, due to repetitive daily or intermittent exposures over several days or weeks, can prolong or exacerbate the transient effects on the baseline respiratory function parameters or alter the lung structure, as a result of the cumulative damage and/or side effect of functional adaptive responses (Christian et al. 1998;Frank et al. 2001). ...
Tropospheric ozone represents a relevant atmospheric pollutant, because of its strong oxidizing potential. The risk for animal
(human) and plant health, at molecular and cellular level, arises from the oxidative damage to lipids, proteins and nucleic
acids, depending on the dose. Therefore, ozone concentration and exposure time determine the chronic or acute toxicity and,
consequently, the severity of injury at biochemical and physiological level. In living organisms, reactive oxygen species
(ROS), directly or indirectly derived from ozone exposure, are scavenged by enzymatic and non-enzymatic antioxidant defensive
mechanisms, overall deputed to preserve cell structures and biomacromolecules from the oxidative damage. These defences are
essentially those also involved in detoxifying the ROS inevitably produced by the metabolism of organisms living in oxygenic
atmosphere.
... Irritants in air pollution, including sulfur dioxide, 15,16 ozone, 17 and formaldehyde (indoor pollutant), 18 but not diesel exhaust particles, 19 have been reported to adversely affect mucociliary clearance. ...
Chronic rhinosinusitis (CRS) affects 12.5% of the US population. On epidemiologic grounds, some association has been found between CRS prevalence and air pollution, active cigarette smoking, secondhand smoke exposure, perennial allergic rhinitis, and gastroesophageal reflux. The majority of pediatric and adult patients with CRS are immune competent. Data on genetic associations with CRS are still sparse. Current consensus definitions subclassify CRS into CRS without nasal polyposis (CRSsNP), CRS with nasal polyposis (CRSwNP), and allergic fungal rhinosinusitis (AFRS). Evaluation and medical management of CRS has been the subject of several recent consensus reports. The highest level of evidence for treatment for CRSsNP exists for saline lavage, intranasal steroids, and long-term macrolide antibiotics. The highest level of evidence for treatment of CRSwNP exists for intranasal steroids, systemic glucocorticoids, and topical steroid irrigations. Aspirin desensitization is beneficial for patients with aspirin-intolerant CRSwNP. Sinus surgery followed by use of systemic steroids is recommended for AFRS. Other modalities of treatment, such as antibiotics for patients with purulent infection and antifungal drugs for patients with AFRS, are potentially useful despite a lack of evidence from controlled treatment trials. The various modalities of medical treatment are reviewed in the context of recent consensus documents and the author's personal experience.
... Although most studies have focused on immune responses in the lung, numerous investigators have provided evidence to support the hypothesis that O3 exposure can have profound effects on systemic (Cellular and Humoral) immunity indices.910 Several indices such as peripheral leukocyte populations’ count are typically elevated after O3 exposure.211–13 Nevertheless, it is generally believed that various physical stressors such as exercise training exert profound effects on total and differential leukocyte counts (leukocytosis).14–16 ...
The immune system in endurance athletes may be at risk for deleterious effects of gasous pollutants such as ambient ozone. Therefore, this study was performed to assess the effect of regular aerobic exercise with ozone exposure on peripheral leukocytes populations in male Wistar rats.
Twenty eight 8 weeks old rats were selected and randomly divided into four groups of ozone-unexposed and untrained (control or group 1, n = 6), ozone-exposed and untrained (group 2, n = 6), ozone-unexposed and trained (group 3, n = 8), ozone-exposed and trained (group 4, n = 8). All animals in groups 3 and 4 were regularly running (20 m/min, 30 min/day) on a treadmill for 7 weeks (5 day/week). After the last ozone exposure [0.3 ppm, 30 min per sessions], blood samples were obtained from the cardiac puncture and hematological parameters as well as blood lactate were measured using automatic analyzers. Data were expressed as means (± SD) and analyzed by ANOVA and Pearson's correlation tests at p < 0.05.
All the hematological parameters differences (except RBC and hemoglobin rate) were significantly higher in the trained groups (p < 0.001). However, ozone-induced leukocytosis in the trained (but not in the sedentary) rats was statistically higher than in the counterpart groups.
Repeated acute ozone exposure has more additive effect on peripheral leukocyte counts in active animals. But, more researches are needed to identify effects of ozone exposure on other components of the immune system in athletes and non-athletes.
... Multi-day exposure studies reveal that an initial enhancement of the nociceptive effect on lung function, followed by an adaptation of this response (41). Additionally, one group reports that repeated exposures causes an adaptation to the neutrophil response to O 3 (42). A second study revealed that repeated exposures caused an influx on macrophages to the airway (with no change in PMNs), suggesting a role for macrophages in regulating innate immune responses to O 3 (43). ...
Ozone (O(3)) and endotoxin are common environmental contaminants that cause asthma exacerbation. These pollutants have similar phenotype response characteristics, including induction of neutrophilic inflammation, changes in airway macrophage immunophenotypes, and ability to enhance response to inhaled allergen. Evoked phenotyping studies of volunteers exposed to O(3) and endotoxin were used to identify the response characteristics of volunteers to these pollutants. New studies support the hypotheses that similar innate immune and oxidant processes modulate response to these agents. These include TLR4 and inflammasome-mediated signaling and cytokine production. Innate immune responses are also impacted by oxidative stress. It is likely that continued discovery of common molecular processes which modulate response to these pollutants will occur. Understanding the pathways that modulate response to pollutants will also allow for discovery of genetic and epigenetic factors that regulate response to these pollutants and determine risk of disease exacerbation. Additionally, defining the mechanisms of response will allow rational selection of interventions to examine. Interventions focused on inhibition of Toll-like receptor 4 and inflammasome represent promising new approaches to preventing pollutant-induced asthma exacerbations. Such interventions include specific inhibitors of innate immunity and antioxidant therapies designed to counter the effects of pollutants on cell signaling.
... In humans and rodents, the acute pulmonary response to O 3 has been characterized, for example, by decreases in lung function parameters, changes in breathing pattern, neutrophil influx, and oxidative stress. Many of the acute O 3 -induced pulmonary responses in humans show physiological adaptive changes following repeated exposures for several days (13,19,20,41). For example, O 3 -induced reductions in forced expiratory volume in 1 sec (FEV 1 ) gradually subside after 2-5 consecutive days of exposure, and this adaptation or loss of response can persist for 2 wk (28). ...
Increased ambient particulate matter (PM) is associated with adverse cardiovascular and respiratory outcomes, as demonstrated by epidemiology studies. Several studies have investigated the role of copollutants, such as ozone (O(3)), in this association. It is accepted that physiological adaptation involving the respiratory system occurs with repeated exposures to O(3). We hypothesize that adaptation to PM and O(3) varies among different inbred mouse strains, and cardiopulmonary adaptation to O(3) is a synchronized response between the cardiac and respiratory systems. Heart rate (HR), HR variability (HRV), and the magnitude and pattern of breathing were simultaneously measured by implanted telemeters and by plethysmography in three inbred mouse strains: C57Bl/6J (B6), C3H/HeJ (HeJ), and C3H/HeOuJ (OuJ). Physiological responses were assessed during dual exposures to filtered air (FA), O(3) (576 +/- 32 parts/billion), and/or carbon black (CB; 556 +/- 34 mug/m(3)). Exposures were repeated for 3 consecutive days. While each strain showed significant reductions in HR during CB with O(3) preexposure (O(3)CB) on day 1, prominent HRV responses were observed in only HeJ and OuJ mice. Each strain also differed in their adaptation profile in response to repeated O(3)CB exposures. Whereas B6 mice showed rapid adaptation in HR after day 1, HeJ mice generally showed more moderate HR and HRV adaptation after day 2 of exposure. Unlike either B6 or HeJ strains, OuJ mice showed little evidence of HR or HRV adaptation to repeated O(3)CB exposure. Adaptation profiles between HR regulation and breathing characteristics were strongly correlated, but these associations also varied significantly among strains. These findings suggest that genetic factors determine the responsivity and adaptation of the cardiac and respiratory systems to repeated copollutant exposures. During O(3)CB exposure, adaptation of cardiac and respiratory systems is markedly synchronized, which may explain a potential mechanism for adverse effects of PM on heart function.
In 2014 we published WHY OZONE THERAPY IN MULTIPLE SCLEROSIS? V. Simonetti, W. Liboni, F. Molinari, Rev. Esp.de OZONOTHERAPY Vol 4, N 1-2014 We have described the results observed on some MS patients treated with ozone therapy. Since then we have strengthened our knowledge on the etiopathogenetic mechanisms of MS and on the importance of the epigenetic factors that influence its manifestation and progression. By reating with OZONE different pathologies, not only in the neurological field, we have expanded the knowledge on the ozone effects 1,2,3,9,10,11,17,18 : we have better understood why ozone therapy can be useful in patients with SM. Compared to what was published in 2014, despite the increase in the number of patients treated by us, from 43 to over 500, the short and long-term results obtained by us and by other colleagues who follow our protocol confirm what we had already published in 2014 12 and in the book we have published 8
This chapter summarizes the nature, history, health effects, regulations, trends, and control of environmental air pollution. Air pollution is a combination of both anthropogenic and natural origins. During the height of the industrial revolution, the health effects of air pollution in cities became apparent. The first federal legislation involving air pollution was the Air Pollution Control Act of 1955, which provided funds for federal research on air pollution. It was followed by the Clean Air Act of 1963, which established a program within the US Public Health Service for research on air pollution monitoring and control techniques. Later, the Air Quality Act of 1967 expanded the federal government's role involving air pollution by enacting enforcement procedures concerning interstate transport of pollutants. The Clean Air Act of 1970 brought about a number of significant changes and has had two amendments. The trends in the level and the health effects of various chemical pollutants have been presented.
Air pollution causes significant morbidity and mortality in patients with inflammatory airway diseases (IAD) such as allergic rhinitis (AR), chronic rhinosinusitis (CRS), asthma, and chronic obstructive pulmonary disease (COPD). Oxidative stress in patients with IAD can induce eosinophilic inflammation in the airways, augment atopic allergic sensitization, and increase susceptibility to infection. We reviewed emerging data depicting the involvement of oxidative stress in IAD patients. We evaluated biomarkers, outcome measures and immunopathological alterations across the airway mucosal barrier following exposure, particularly when accentuated by an infectious insult.
Bronchial asthma is characterized by airway inflammation, airway hyperresponsiveness to several specific and nonspecific stimuli, and reversible airway obstruction with the appearance of respiratory symptoms, such as dyspnea, chest tightness, wheezing, and cough. Although the pathogenesis of bronchial asthma is not completely understood, it is evident that this clinical condition has a multifactorial etiology, and a body of evidence suggests that bronchial asthma has become more common worldwide in recent years (1–2). There is a link between the increase in the prevalence of allergic airway diseases and the increase in air pollution. Several studies have shown the adverse effects of ambient air pollution on respiratory health (3–10). Moreover, exposure to components of air pollution enhances the airway response to inhaled allergens in susceptible individuals and, in most industrialized countries, people who live in urban areas are more affected by allergic respiratory diseases than those who live in rural areas (11,12). Road traffic, with its gaseous and particulate emissions, is currently, and likely to remain, the main contributor to air pollution in most urban settings (13–16).
Even if the reader has only browsed through the previous chapters, he ought to have received my feeling that ozone has an enormous therapeutic potential that, so far, has been either disregarded, if not obstructed by world medical authorities. Reasons for delaying the use of ozone are multiple: while quacks and inexpert ozonetherapists are at fault for poor work, other aspects such as commercial and pharmaceutical interests, prejudice, lack of knowledge and a myopic medical vision have done their best to block a substantial and rapid progress.
The present article summarizes about the air pollution and several legislations for its monitoring and control. Air pollution is a combination of both anthropogenic and natural origins and during the height of the industrial revolution that the health effects of air pollution in the cities became apparent. The first federal legislation involving air pollution was the Air Pollution Control Act of 1955 and provided funds for federal research on air pollution and followed by the Clean Air Act of 1963, which established a program within the U.S. Public Health Service for research on air pollution monitoring and control techniques. Later, the Air Quality Act of 1967 expanded the federal government's role involving air pollution by enacting enforcement procedures concerning interstate transport of pollutants. The Clean Air Act of 1970 brought about a number of significant changes and also undergone two amendments. The trends of the level and health effects of various chemical pollutants have been presented.
Airway response to the external environment forms the basis for many airway/lung diseases such as asthma and chronic obstructive airways disease (COPD) which are characterized by chronic airflow obstruction, chronic airway inflammation and tissue remodeling. Allergic inflammation and oxidative stress contribute to airways dysfunction and direct effects of these processes have been demonstrated in human and animal models. Airway responses to allergens and to environmental pollution such as ozone represent a mixture of innate and adaptive immune responses. Through the release of inflammatory cytokines and expression of co-stimulatory molecules, and antigen presentation, innate immune cells such as dendritic cells can interact with CD4 T-cells and direct their maturation program. The oxidant, ozone, can also utilize innate immune recognition pathways through toll-like receptors and activate a range of innate immune cells including dendritic cells (DCs), macrophages, and immune responses. Crosstalk between these two responses is likely to be common occurrence as exposure to oxidants is unavoidable in urban environments with high levels of pollution and allergic inflammation is a potential source of oxidants. The interaction of ozone and allergen offers interesting perspectives in unraveling further the interactions of innate and adaptive responses that could form the basis of chronic airway diseases of chronic airflow obstruction and inflammation.
Background:
Inhalation of ambient levels of ozone causes airway inflammation and epithelial injury.
Methods:
To examine the responses of airway cells to ozone-induced oxidative injury, 19 subjects (7 with asthma) were exposed to clean air (0ppb), medium (100ppb), and high (200ppb) ambient levels of ozone for 4h on three separate occasions in a climate-controlled chamber followed by bronchoscopy with bronchoalveolar lavage (BAL) 24h later. BAL cell mRNA expression was examined using Affymetrix GeneChip Microarray. The role of a differentially expressed gene (DEG) in epithelial injury was evaluated in an in vitro model of injury [16HBE14o- cell line scratch assay].
Results:
Ozone exposure caused a dose-dependent up-regulation of several biologic pathways involved in inflammation and repair including chemokine and cytokine secretion, activity, and receptor binding; metalloproteinase and endopeptidase activity; adhesion, locomotion, and migration; and cell growth and tumorigenesis regulation. Asthmatic subjects had 1.7- to 3.8-fold higher expression of many DEGs suggestive of increased proinflammatory and matrix degradation and remodeling signals. The most highly up-regulated gene was osteopontin, the protein level of which in BAL fluid increased in a dose-dependent manner after ozone exposure. Asthmatic subjects had a disproportionate increase in non-polymerized osteopontin with increasing exposure to ozone. Treatment with polymeric, but not monomeric, osteopontin enhanced the migration of epithelial cells and wound closure in an α9β1 integrin-dependent manner.
Conclusions:
Expression profiling of BAL cells after ozone exposure reveals potential regulatory genes and pathways activated by oxidative stress. One DEG, osteopontin, promotes epithelial wound healing in an in vitro model of injury.
Oxygen-Ozone therapy is a complementary approach less known than homeopathy and acupuncture because it has come of age only three decades ago. This book clarifies that, in the often nebulous field of natural medicine, the biological bases of ozone therapy are totally in line with classical biochemistry, physiological and pharmacological knowledge. Ozone is an oxidizing molecule, a sort of super active oxygen, which, by reacting with blood components generates a number of chemical messengers responsible for activating crucial biological functions such as oxygen delivery, immune activation, release of hormones and induction of antioxidant enzymes, which is an exceptional property for correcting the chronic oxidative stress present in atherosclerosis, diabetes and cancer. Moreover, by inducing nitric oxide synthase, ozone therapy may mobilize endogenous stem cells, which will promote regeneration of ischemic tissues. The description of these phenomena offers the first comprehensive picture for understanding how ozone works and why. When properly used as a real drug within therapeutic range, ozone therapy does not only does not procure adverse effects but yields a feeling of wellness. Half the book describes the value of ozone treatment in several diseases, particularly cutanious infection and vascular diseases where ozone really behaves as a "wonder drug". The book has been written for clinical researchers, physicians and ozone therapists, but also for the layman or the patient interested in this therapy.
Ozone is a very unstable and reactive molecule that can rapidly oxidize many organic substances and is often used for odor control. It is also known to be an effective biocide at high dose levels. Despite the lack of scientific evidence linking ozone to reduced aerial ammonia at levels that are safe for birds and humans, there is still an interest in the use of the product for commercial production poultry units. The objective of this experiment was to determine the effect of adding atmospheric ozone at a target level of 0.05 ppm (level achieved, 0.03 +/- 0.017 ppm) to rooms housing broiler chickens. Female broiler chickens were grown in either an untreated environment or an environment with added ozone (3 rooms of 5 replicate pens, each containing 110 birds/treatment). Bird weight and feed consumption were recorded on a pen basis at 21 and 40 d of age; mortalities were collected daily, and necropsies were performed. Air samples were collected and plated on appropriate media to count total aerobic bacteria at 11, 19, and 34 d of age and enterobacteria at 34 d. Atmospheric ammonia levels were measured on d 15, 20, 28, 32, and 38. A significant (P = 0.05) improvement in feed conversion (feed: gain ratio) when corrected for mortality was noted in the ozone-treated birds (1.808 vs. 1.870). Birds exposed to ozone grew significantly slower (1.938 vs. 2.053 kg of BW gain), consumed less feed (3.695 vs. 3.953 kg), and had a higher mortality (11.46 vs. 7.33%) and condemnation percentages (10.36 vs. 3.39%) than nontreated broilers. The addition of ozone caused no significant decrease in ammonia level or total bacterial count. The major increases in morbidity and mortality of the birds subjected to ozone make ozone gas unacceptable for use in a commercial broiler unit and raise serious health issues for both producers and birds.
Chronic purulent rhinosinusitis (CPR) is an inflammatory condition of unknown origin. Although various medical and surgical treatment modalities are available, 5-10% of patients remain refractory. Immune deficiency is one of the underlying risk factors for this disease. Earlier studies demonstrated disturbances in cell-mediated immunity and defects in monocyte chemotaxis in CPR. Treatment with the thymic hormone preparation thymostimulin led to significant clinical improvement in patients and in vitro restoration of monocyte chemotaxis. Unfortunately, thymostimulin became unavailable, which has led to recent interest in the immunomodulatory effects of the thymic peptide thymosin α1, which has demonstrated some benefit for CPR. Our current in vitro work focuses on the potential effects of thymosin α1 on monocyte function and gene expression profiles in order to understand its effects and mechanisms of action. Future clinical studies will evaluate the potential significance of thymosin α1 in treatment of CPR patients.
Clinical tolerance to the acute effects of zinc oxide inhalation develops in workers during periods of repeated exposure. The aims of this study were to determine whether clinical tolerance is accompanied by a reduction in the acute pulmonary inflammatory and cytokine responses to zinc oxide exposure and whether tolerance can be demonstrated in sheet metal workers who chronically inhale low levels of zinc oxide. Naive (never-exposed) subjects inhaled 5 mg/m3 zinc oxide on 1 or 3 days and underwent bronchoalveolar lavage 20 hours after the final exposure. Sheet metal workers inhaled zinc oxide on 1 day and control furnace gas on another day. Among naive subjects in whom tolerance was induced, bronchoalveolar lavage fluid percent neutrophils and interleukin-6 (IL-6) levels were significantly decreased compared with subjects who underwent only a single exposure. Sheet metal workers were much less symptomatic, but they still experienced a significant increase in plasma IL-6. The results indicate that clinical tolerance to zinc oxide is accompanied by reduced pulmonary inflammation and that chronically exposed sheet metal workers are not clinically affected by exposure to zinc oxide fume at the Occupational Safety and Health Administration Permissible Exposure Limit. The increase in IL-6 levels observed in the clinically responsive, and to a lesser extent, tolerant, states following zinc oxide inhalation is consistent with the dual role of IL-6 as a pyrogen and anti-inflammatory agent.
Air pollution is a result of global warming, greenhouse effects, and acid rain. Especially in highly industrialization areas, air pollution has become a major environmental issue. Poor air quality has both acute and chronic effects on human health. The detrimental effects of ambient ozone on human health and the Earth’s ecosystem continue to be a national concern in Taiwan. The pollutant standard index (PSI) has been adopted to assess the degree of air pollution in Taiwan. The standardized daily air quality report provides a simple number on a scale of 0 to 500 related to the health effects of air quality levels. The report focuses on health and the current PSI subindices to reflect measured ozone (O3) concentrations. Therefore, this study uses the O3 attribute to evaluate air quality. In an effort to forecast daily maximum ozone concentrations, many researchers have developed daily ozone forecasting models. However, this continuing worldwide environmental problem suggests the need for more accurate models. This paper proposes two new fuzzy time series based on a two-stage linguistic partition method to predict air quality with daily maximum O3 concentration: Stage 1, use the fuzzy time series based on the cumulative probability distribution approach (CPDA) to partition the universe of discourse into seven intervals; Stage 2, use two linguistic partition methods, the CPDA and the uniform discretion method (UDM), to repartition each interval into three subintervals. To verify the forecasting performance of the proposed methods in detail, the practical collected data is used as and evaluating dataset; five other methodologies (AR, MA, ARMA, Chen’s and Yu’s) are used as comparison models. The proposed methods both show a greatly improved performance in daily maximal ozone concentration prediction accuracy compared with the other models.
Epidemiological studies show positive associations between increased ambient air pollutant levels and adverse cardiopulmonary effects. These studies suggest that the elderly and those with certain genetic polymorphisms are susceptible to adverse air pollution-associated health events. Hypothesis/objective: We hypothesize that physiological responses to air pollutants vary with age and are genetically influenced.
To test this hypothesis, we exposed mice from three inbred strains (C57BL/6J, B6; C3H/HeJ, HeJ; C3H/HeOuJ, OuJ) to ozone (O(3)) and carbon black (CB) at two ages, (5 months, 12 months), for 3 consecutive days, to either filtered air (FA), CB particles, or O(3) and CB sequentially (O(3)CB) (CB, 550 µg/m(3); O(3), 600 ppb). Heart rate (HR), HR variability (HRV), breathing, and core temperature (Tco) responses were analyzed. Results: We observed time-dependent physiological changes in response to O(3)CB exposure in each strain, relative to FA exposure for both age groups. Each mouse strain showed distinct adaptation profiles to repeated acute exposures to O(3). In younger mice, several time-dependent effects (decreased HR and increased HRV) were prominent in HeJ and OuJ mice but not B6 mice. We also observed variability in adaptation in older mice. However, responses in older mice were generally attenuated when compared to the younger mice. In addition, cardiac-respiratory interactions were affected with CB and O(3)CB exposures albeit with patterns differing by age or exposure.
Our results suggest that age considerably attenuates physiological responses to O(3) and O(3)CB exposures. Age-related physiological changes such as increased oxidative stress in mouse tissue may be involved in this attenuation.
Elevated levels of ambient co-pollutants are associated with adverse cardiovascular outcomes shown by epidemiology studies. The role of particulate matter (PM) and ozone (O3) as co-pollutants in this association is unclear. We hypothesize that cardiac function following PM and O3 exposure is variably affected by genetic determinants (Nppa and Npr1 genes) and age. Heart function was measured before and after 2 days each of the following exposure sequence; (1) 2-h filtered air (FA) and 3-h carbon black (CB; 0.5 microg/m(3)); (2) 2-h O3 (0.6 ppm) and 3-h FA; (3) 5-h FA; and, (4) 2-h O3 and 3-h CB. Two age groups (5 and 18 months old (mo)) were tested in C57Bl/6J (B6) and 129S1/SvImJ (129) mice using echocardiographic (echo) and in vivo hemodynamic (IVH) measurements. With echo, posterior wall thickness was significantly (P < 0.01) greater in 129 relative to B6 mice at baseline. With CB exposure, young B6 and older 129 mice show significant (P < 0.01) reductions in fractional shortening (FS) compared to FA. With O3 exposure, FS was significantly (P < 0.01) diminished in young 129, which was attributable to significant increases in end-systolic left ventricular diameter. With O3 and CB combined, notable (P < 0.01) declines in heart rate and end-systolic posterior wall thickness occurred in young 129 mice. The IVH measurements showed striking (P < 0.05) compromises in cardiac function after CB and O3 exposure; however, strain differences were undetectable. These results suggest that PM and O3 exposures, alone and combined, lead to different cardiac functional changes, and these unique changes are age-specific and dependent on Nppa and Npr1 genes.
Large urbanized areas, where sports events take place, have a polluted environment and can also reach high temperatures and humidity levels. The aim of this study was to investigate the impact of a hot, humid and ozone-polluted (O(3)) environment on (1) performance of an 8 km time trial run, (2) pulmonary function, and (3) subjective respiratory symptoms in endurance-trained runners. Using crossover randomized design, 10 male participants (mean V(O)₂(max)= 64.4 mlO(2) kg(-1) min(-1), SD = 4.4) took part in a time trial run under four different conditions: 20 degrees C + 50% relative humidity (rh) (Control), 20 degrees C + 50% rh + 0.10 ppm O(3) (Control + O(3)), 31 degrees C + 70% rh (Heat), 31 degrees C + 70% rh + 0.10 ppm O(3) (Heat + O(3)). Heart rate, ratings of perceived exertion and minute ventilation were collected during the run. Lung function was measured pre and post-exercise. The runners completed a respiratory symptoms questionnaire after each trial. The completion time of both the Heat (32 min 35 s) and Heat + O(3) (33 min 09 s) trials were significantly higher (P < 0.0001) when compared to the Control + O(3) (30 min 27 s) and Control (30 min 15 s) trials. There were no significant changes between pre/post lung function measures or between trials. The effective dose of ozone simulated in the present study did not affect the performance and therefore, ozone-pollution, at an environmentally relevant concentration, did not compound the impairment in performance beyond that induced by a hot, humid environment.
The effects of low-level ozone exposure (0.08 ppm) on pulmonary function in healthy young adults are well known; however, much less is known about the inflammatory and immunomodulatory effects of low-level ozone in the airways. Techniques such as induced sputum and flow cytometry make it possible to examine airways inflammatory responses and changes in immune cell surface phenotypes following low-level ozone exposure. The purpose of this study was to determine if exposure to 0.08 parts per million ozone for 6.6 h induces inflammation and modifies immune cell surface phenotypes in the airways of healthy adult subjects. Fifteen normal volunteers underwent an established 0.08 part per million ozone exposure protocol to characterize the effect of ozone on airways inflammation and immune cell surface phenotypes. Induced sputum and flow cytometry were used to assess these endpoints 24 h before and 18 h after exposure. The results showed that exposure to 0.08 ppm ozone for 6.6 h induced increased airway neutrophils, monocytes, and dendritic cells and modified the expression of CD14, HLA-DR, CD80, and CD86 on monocytes 18 h following exposure. Exposure to 0.08 parts per million ozone is associated with increased airways inflammation and promotion of antigen-presenting cell phenotypes 18 hours following exposure. These findings need to be replicated in a similar experiment that includes a control air exposure.
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BACKGROUND : The immune system in endurance athletes may be at risk for deleterious effects of gasous pollutants such as ambient ozone. Therefore, this study was performed to assess the effect of regular aerobic exercise with ozone exposure on peripheral leukocytes populations in male Wistar rats.
METHODS : Twenty eight 8 weeks old rats were selected and randomly divided into four groups of ozone-unexposed anduntrained (control or group 1, n = 6), ozone-exposed and untrained (group 2, n = 6), ozone-unexposed and trained (group 3, n = 8), ozone-exposed and trained (group 4, n = 8). All animals in groups 3 and 4 were regularly running (20 m/min, 30 min/day) on a treadmill for 7 weeks (5 day/week). After the last ozone exposure [0.3 ppm, 30 min per sessions], blood samples were obtained from the cardiac puncture and hematological parameters as well as blood lactate were measured using automatic analyzers. Data were expressed as means (± SD) and analyzed by ANOVA and Pearson's correlation tests at p < 0.05.
RESULTS : All the hematological parameters differences (except RBC and hemoglobin rate) were significantly higher in the trained groups (p < 0.001). However, ozone-induced leukocytosis in the trained (but not in the sedentary) rats was statistically higher than in the counterpart groups.
CONCLUSIONS : Repeated acute ozone exposure has more additive effect on peripheral leukocyte counts in active animals. But, more researches are needed to identify effects of ozone exposure on other components of the immune system in athletes and non-athletes.
KEYWORDS : Moderate Aerobic Exercise, Ozone Exposure, eukocytosis, Wistar Rats. </ul
Ozon verursacht als wichtiger Luftschadstoff pathologische Veränderungen des Respirationssystems sowie Einschränkungen der Lungenfunktion. Seine Toxizität beruht dabei auf seiner hohen Oxidationskraft mit Auslösung eines „oxidativen Stresses“. Dieser besteht auch unabhängig von Ozon bei Entzündungsreaktionen und wird als wichtige pathogene Komponente bei der Entstehung verschiedener Lungenerkrankungen wie beispielsweise dem Asthma bronchiale und der COPD postuliert. Heat Schock Proteine (HSPs) werden nach Exposition mit Stress-Faktoren wie beispielsweise Hyperthermie, Inflammation und oxidativem Stress gebildet und können daher als Parameter für zellulären Stress angesehen werden. Ambroxol wird als mukolytisches Medikament bei Atemwegserkrankungen eingesetzt. Diesem Wirkstoff werden u.a. auch antioxidative Eigenschaften zugeschrieben. Ziel dieser Arbeit ist es, die ozonvermittelte Stressantwort (HSP 32, -60, -70 und HSC 70) in der Lunge sowie eine eventuelle Protektion durch zusätzliche Ambroxolgabe zu untersuchen. Dazu wurden Sprague Dawley Ratten Ozon in unterschiedlicher Konzentration und Dauer (8h mit 1,5 bzw. 3ppm oder 12h bzw. 24h mit 0,6ppm) mit und ohne Ambroxolgabe ausgesetzt und anschließend die HSP Protein- und m-RNA-Expression im Gesamtlungengewebe mittels Western Blot und PCR bestimmt. Die zeit- und konzentrationsabhängige Zunahme der HSP 32-Expression nach Ozonexposition (360%-989,3%) wurde durch eine zusätzliche Ambroxolgabe gehemmt (119,8%). Unter Ozonexposition war vermehrt HSP 70 m-RNA (163,4%-249,8%) bei allerdings stark verminderter HSP 70 Konzentration (10,7%-53,7%) nachweisbar. Bei zusätzlich verabreichtem Ambroxol war der Proteinabfall weniger stark ausgeprägt (46,5%-69%). Die Proteinkonzentrationen von HSC 70 und HSP 60 stellen sich insbesondere bei den kürzeren Expositionszeiten (8 und 12h) vermindert dar (9,3%-55,3% bzw. 40,2%-76,3%). Unter zusätzlicher Ambroxolgabe war die Ozon-bedingte Verminderung des HSC 70 geringer ausgeprägt (61,3%), bei HSP 60 war kein eindeutiger Effekt auf die Proteinexpression nachweisbar. Eine alleinige Ambroxolgabe bewirkte eine Hemmung von HSP 70 und HSP 60, HSP 32 war nach Ambroxolapplikation vermehrt nachweisbar, während HSC 70 kaum durch Ambroxol beeinflusst wurde. Die Ergebnisse zeigen unterschiedliche Auswirkungen der Ozonexposition auf die verschiedenen HSPs. Ozon bewirkte eine erhöhte HSP 32 Expression, zudem war eine verstärkte Induktion der HSP 70 mRNA durch Ozon zu beobachten. HSC 70 und HSP 60 hingegen waren nach Ozon vermindert nachweisbar. Möglicherweise zeigt diese Hemmung eine Prioritätensetzung zugunsten anderer HSPs auf. Ambroxol verminderte die Ozonbedingte HSP 32 Stressantwort. Diese Beobachtung unterstreicht das Postulat von Ambroxol als eine potente antioxidative Substanz mit möglicher protektiver Wirkung auf das Lungengewebe. Ozone is an important air pollutant that compromises lung function and causes acute lung injury. Cellular injury induces stress related expression of several high conserved proteins. Of those proteins one important group consisits of the heat shock proteins (HSP). Ambroxol, often used in respiratory diseases, is postulated to provide antioxidant properties. To investigate the stress response in ozone-induced lung injury and the potential protection by ambroxol, we analyzed HSP´s protein and mRNA expression in rat whole lung tissue after ozone exposure, with and without ambroxol treatment. Two groups of Sprague Dawley rats (5 each) were exposed to 3ppm ozone for 8 hours. One group was treated with ambroxol, while the other was not. Two groups (6 each) of control animals were not exposed to ozone, either treated with ambroxol or not. Heat shock protein (HSP 32, -60, -70, -73kD) and mRNA expression were analyzed using specific immunoblot and competive PCR. GAPDH were used to normalize mRNA. HSP 32 protein (436%) and mRNA (536%) were significantly increased in ozone exposed animals (% of controls), while exposed animals treated with ambroxol showed dignificant reduction in protein amount (119%). HSP 60 (40,2%), -70 (10,6%) and -73 (9,3%) protein were significant decreased after ozone exposure. This decrease was inhibited by ambroxol in part (HSP 60; 75,8%, HSP 73: 61,3%, HSP 72: 46,5%). HSP 72 mRNA was elevated in ozone exposed animals (248%) with further increase in those teated with ambroxol, while HSP 60 and 73 mRNA were not significantly changed. Ozone induced lung injury results in HSP 32 expression and decreases HSP 60/72/73, while both is inhibited by ambroxol, suggesting that ambroxol may work as an potent antioxidant.
Clara cell protein (CC16) is a 16-17-kDa protein secreted by Clara cells in the bronchial lining fluid of the lung from which it passively diffuses into serum before being eliminated by the kidneys. The concentration of CC16 in serum has recently been proposed as a peripheral marker of the integrity of Clara cells and/or of the bronchoalveolar/blood barrier. To evaluate the sensitivity of this new lung marker to acute epithelial damage induced by ozone (O(3)), CC16 was determined in the serum of rats after a single 3-h exposure to 0.3, 0.6, or 1 ppm O(3). The urinary excretion of the protein was also studied in rats repeatedly exposed to 1 ppm O(3), 3 h/day, for up to 10 days. The concentrations of CC16 in the lung or trachea homogenates, the lung CC16 mRNA levels, and classical markers of lung injury in bronchoalveolar lavage fluid (BALF) were also determined. O(3) produced a transient increase of CC16 concentration in serum that reached values on average 13 times above normal 2 h after exposure to 1 ppm O(3). The intravascular leakage of CC16 was dose-dependent and correlated with the extent of lung injury as assessed by the levels of total protein, LDH, and inflammatory cells in BALF. This effect was most likely responsible for the concomitant marked reduction of CC16 concentrations in BALF and lung homogenate, since the CC16 mRNA levels in the lungs were unchanged and the absolute amounts of CC16 leaking into serum or lost from the respiratory tract were similar. These changes were paralleled by an elevation of the urinary excretion of CC16 resulting from an overloading of the tubular reabsorption process. These results demonstrate that the assay of CC16 in serum and even in urine represents a new noninvasive test to detect the increased lung epithelial permeability induced by O(3).
Asthmatic individuals appear to be particularly sensitive to the effects of certain air pollutants-including ozone (O(3)), an oxidant ambient air pollutant-for reasons that are poorly understood. The general purpose of these studies, therefore, was to expand and improve upon toxicologic methods for assessing ozone-induced effects on the airways of the rat by (1) developing an in vivo testing procedure that allows detection of airway responsiveness changes in rats exposed to ozone; (2) identifying a strain of rat that may be inherently more sensitive to the effects of ozone; and (3) validation of an in vitro epithelial culture system to more directly assess airway cellular/subcellular effects of ozone. Using methacholine inhalation challenges, we detected increased airway responsiveness in senescent F344 rats acutely after ozone exposure (2 ppm x 2 h). We also determined that acutely after ozone exposure (0.5 ppm x 8 h), Wistar rats developed significantly greater lung injury, neutrophilic inflammation, and bronchoalveolar lavage (BAL) fluid concentrations of IL-6 than either Sprague-Dawley (SD) or F344 rats. SD rats had greater BAL fluid concentrations of prostaglandin E(2) (PGE(2)), while F344 rats consistently exhibited the least effect. Wistar rat-derived tracheal epithelial (RTE) cultures were exposed in vitro to air or ozone (0.1-1.0 ppm x 1 h), and examined for analogous effects. In a concentration-dependent manner, ozone exposure resulted in acute but minor cytotoxicity. RT polymerase chain reaction (PCR) analysis of RNA isolated from ozone-exposed cells demonstrated variable increases in steady-state gene expression of IL-6 at 4 h postexposure, while at 24 h cellular fibronectin expression (EIIIA domain) was decreased. Exposure was without effect on macrophage inflammatory protein 2 (MIP-2) or gamma-glutamyl cysteine synthetase expression. At 6 h postexposure, IL-6 synthesis and apical release appeared increased in ozone-exposed cells (1 ppm x 1 h). MIP-2 release was not significantly increased in ozone-exposed cells. At 2 h postexposure, ozone exposure resulted in minor increases in apical fibronectin, but exposure was without effect on basolateral accumulation of fibronectin. Exposure to 1.0, but not 0.1 ppm (x 1 h), increased production of cyclooxygenase (i.e., PGE(2)) and noncyclooxygenase products of arachidonic acid. Results demonstrate that multiple inflammatory mediator pathways are affected by ozone exposure. Such effects could exacerbate morbidity in individuals with preexisting airway inflammation such as asthmatics.
In this review it has been demonstrated that exposure to air pollutants in workroom and ambient concentrations are important inducers of airway inflammation in healthy subjects. It is suggested that antioxidants present in the ELF may play a role in modulating the impact of oxidative air pollutants on the airways. The upregulation of vascular adhesion molecules and secretion of pro-inflammatory cytokines may be of importance in mediating the inflammatory response in the airways after exposure to air pollutants. Future studies are needed to study lower concentrations and, if possible, determine threshold levels for the noxious effects of the air pollutants. Furthermore, epidemiological and clinical data suggest that people with asthma, allergy and other respiratory illnesses appear to represent more sensitive groups with respect to air pollution. Thus it is of importance to investigate the mechanisms behind the inflammatory changes in the airways following exposure to air pollutants both in healthy and in sensitive groups in more detail.
Humans exposed to ozone a single time develop decrements in lung function and an inflammatory reaction in the lung characterized by increased numbers of neutrophils and increased amounts of soluble mediators of inflammation such as interleukin (IL)-8, IL-6, prostaglandin (PG) E2, lactate dehydrogenase, elastase, and lung protein in bronchoalveolar lavage fluid (BALF). However, humans who undergo repeated daily exposures to ozone have decrements in lung function on days 1 and 2 of exposure, followed by progressive diminution or even complete disappearance on following days, a process termed 'attenuation' or 'tolerance'. It is not known whether repeated exposure of humans to ozone also results in attenuation of the inflammatory response. In this study, 16 healthy young adult males were exposed to air and 0.4 ppm ozone for 2 h/day on 5 consecutive days, and again a single time 10 or 20 days after the initial 5-day ozone exposure. Bronchoalveolar lavage (BAL) was performed after 5 days of ozone exposure, after 5 days of air exposure, and a third time after the 10- or 20-day follow-up ozone exposure. Ozone-induced increases in percent polymorphonuclear leukocytes (PMNs) and BALF levels of IL-6, PGE2, elastase, and fibronectin were diminished after 5 days of exposure. In addition, ozone-induced decreases in recovery of viable BALF cells and alveolar macrophage phagocytosis of yeast were also blunted. However, lactate dehydrogenase (LDH), elastase, IL-8, BALF total protein, α1-antitrypsin, and percent epithelial cells were not diminished. Reversal of ozone-induced attenuation was complex. Some mediators (PMNs, IL-6, PGE2, fibronectin, recovery of viable cells) showed at least partial, if not complete, reversal within 10-20 days, while others (total protein, α1-antitrypsin) did not return to the normal response to ozone even after 20 days. We conclude from this study that increases in many cellular and biochemical mediators indicative of inflammation seen after a single exposure of humans to ozone are attenuated after 5 consecutive days of exposure. This attenuation is similar to attenuation of symptoms and lung function reported previously. However, markers of cell injury (increased epithelial cells, LDH, total protein) are not attenuated, and may indicate a persistent but not perceived effect of ozone.
Acute ozone (O3) exposure in humans produces changes in pulmonary function that attenuate with repeated exposure. This phenomenon, termed adaptation, has been produced in unanesthetized rats. Rats exposed to O3 (0, 0.35, 0.5, or 1.0 ppm) for 2.25 h for 5 consecutive days showed an increased frequency of breathing and a decreased tidal volume on Days 1 and 2 of exposure at all O3 concentrations. However, by Day 5 these breathing responses to O3 were diminished in rats exposed to 0.35 and 0.5 ppm, but not in rats exposed to 1.0 ppm. In addition, a flow limitation in smaller airways was observed after the second day of exposure to 0.5 ppm O3 that initially attenuated and then disappeared by the fifth day of exposure. In contrast to these findings, a light microscopic examination of fixed lung tissue sections from rats exposed to 0.5 ppm indicated a 5-day progressive pattern of epithelial damage and inflammation in the terminal bronchiolar region. A sustained 37% increase in lavageable protein was also observed over the course of the 5-day exposure regimen to 0.5 ppm. Lung glutathione increased initially, but it was within the control range on Days 4 and 5. Lung ascorbate was significantly elevated above control levels on Days 3 and 5. These data suggest that attenuation of the pulmonary function response to O3 occurs in laboratory rats with repeated exposure while biochemical and morphologic aspects of the tissue response continue to progress.
Although ozone (O3) has been shown to induce inflammation in the lungs of animals, very little is known about its inflammatory effects on humans. In this study, 11 healthy nonsmoking men, 18 to 35 yr of age (mean, 25.4 +/- 3.5), were exposed once to 0.4 ppm O3 and once to filtered air for 2 h with intermittent exercise. Eighteen hours later, bronchoalveolar lavage (BAL) was performed and the cells and fluid were analyzed for various indicators of inflammation. There was an 8.2-fold increase in the percentage of polymorphonuclear leukocytes (PMN) in the total cell population, and a small but significant decrease in the percentage of macrophages after exposure to O3. Immunoreactive neutrophil elastase often associated with inflammation and lung damage increased by 3.8-fold in the fluid while its activity increased 20.6-fold in the lavaged cells. A 2-fold increase in the levels of protein, albumin, and IgG suggested increased vascular permeability of the lung. Several biochemical markers that could act as chemotactic or regulatory factors in an inflammatory response were examined in the BAL fluid (BALF). The level of complement fragment C3 alpha was increased by 1.7-fold. The chemotactic leukotriene B4 was unchanged while prostaglandin E2 increased 2-fold. In contrast, three enzyme systems of phagocytes with potentially damaging effects on tissues and microbes, namely, NADPH-oxidase and the lysosomal enzymes acid phosphatase and beta-glucuronidase, were increased neither in the lavaged fluid nor cells. In addition, the amounts of fibrogenic-related molecules were assessed in BALF.(ABSTRACT TRUNCATED AT 250 WORDS)
We exposed eight normal adults to filtered air (FA) and 0.35 ppm ozone (O3) and compared responses in spirometry, including isovolume (isoV) flows at intermediate-to-low lung volumes, against levels of inflammatory markers in bronchoalveolar lavage fluid (BALF) and peripheral lung resistance (Rp) measured through a wedged bronchoscope. Spirometry was performed at the end, 25 min and 24 h after exposure, bronchoscopy at 24 h after exposure. The percentages of neutrophils, fibrinogen, albumin, PGE2, PGF2 alpha, and kinins were elevated in BALF after O3 compared with FA. The percentage reduction in (isoV) FEF25-75 at 25 min and 24 h after administration of O3 correlated closely with the rise in fibrinogen concentrations in BALF, a marker of altered vascular permeability. Rp, a measurement dominated by very small or peripheral airways, was unaffected in 7 of 8 subjects. The absence of change in Rp might have reflected insufficient penetration of O3 into these airways to produce or sustain an effect for 24 h; alternatively, the bronchoscopic procedure which included atropine and lidocaine pretreatment may have reversed an O3 effect. An unexpected finding was the significant association between baseline Rp (after FA) and the magnitude of the spirometric response to O3. Our results suggest that small airway dysfunction in the immediate post-O3 period is a marker of lung inflammation.
Controlled human exposure studies have suggested that the National Ambient Air Quality Standard for ozone (O3) may not provide a margin of safety to protect the most susceptible members of the population from adverse health effects. Although the subgroups of the population that are most susceptible to O3 have not been identified, recent work in our laboratory suggested that methacholine responsiveness might be an important determinant of susceptibility to O3.
To test the hypothesis that methacholine responsiveness is correlated with FEV1 response after O3 exposure, we conducted methacholine challenge tests and O3 (0.20 ppm) and filtered air exposures for 4 h with moderate exercise on 66 healthy individuals.
Repeated measures analysis of variance demonstrated significant changes in FEV1 (-0.82 +/- 0.63 L), FVC (-0.69 +/- 0.48 L), and specific airway resistance (SRaw) (+1.5 +/- 1.1 L x cm H2O/L/s) across the O3 exposure that persisted after adjusting for responses to air. Baseline PC100 (the concentration of methacholine that caused a doubling of the baseline SRaw) was weakly associated with O3-induced increases in SRaw (F1.54 = 2.85, p = 0.09), but not O3-induced declines in FEV1 or FVC. There was a weak association (r = -0.29) between O3-induced responses for SRaw and FEV1. The FEV1 responses for O3 were weakly associated with the symptoms of cough (r = -0.37), wheeze (r = -0.29), chest pain on deep inspiration (r = -0.31), and shortness of breath (r = -0.37), but not with chest discomfort or sputum production.
Although we were unable to find support for our hypothesis, we found, somewhat surprisingly, that respiratory symptoms were weakly associated or unassociated with FEV1 responses after O3 exposure. This finding implies that individuals may experience adverse effects, ie, respiratory symptoms, without large declines in lung function. Conversely, individuals may suffer large declines in lung function without prominent symptoms and, therefore, may remain in an unhealthy environment despite evidence of toxicity.
Humans exposed to ozone a single time develop decrements in lung function and an inflammatory reaction in the lung characterized by increased numbers of neutrophils and increased amounts of soluble mediators of inflammation such as interleukin (IL)-8, IL-6, prostaglandin (PG) E, lactate dehydrogenase, elastase, and lung protein in bron2 choalveolar lavage fluid (BALF). However, humans who undergo repeated daily expo- sures to ozone have decrements in lung function on days 1 and 2 of exposure, followed by progressive diminution or even complete disappearance on following days, a process termed "attenuation" or "tolerance." It is not known whether repeated exposure of humans to ozone also results in attenuation of the inflammatory response. In this study, 16 healthy young adult males were exposed to air and 0.4 ppm ozone for 2 h/day on 5 consecutive days, and again a single time 10 or 20 days after the initial 5-day ozone exposure. Bronchoalveolar lavage (BAL) was performed after 5 days of ozone exposure, a...
Correlation of ozone aerometrics with data from health effect studies on ozone suggests that the present ozone standard is inadequate to protect public health. To develop ozone exposure-effect relationships, the present study was performed to determine the effects of ozone in rats following prolonged, episodic exposure. Acute pulmonary injury and inflammation, as assessed by lung lavage protein increase and neutrophil influx, following 3 consecutive, 12 h nocturnal exposures to 0.4 ppm appeared to be primarily induced by the first exposure and showed full reversibility in spite of continuance of exposure. Biochemical indices for cell proliferation and lung tissue repair, however, showed continual increases during consecutive exposures. Assessment of characteristic cell functions in isolated Clara cells and in alveolar macrophages and type II cells following continuous ozone exposure to 0.8 ppm (7 days) or 0.75 ppm (4 days), respectively, revealed that lung cell proliferation coincides with cellular biochemical changes which might be looked upon as potentially adverse. Collectively, these data call upon health risk evaluations of episodic ozone effects and reinforce the need for extension of the data base in this respect.
A study was undertaken to find the optimal conditions for generating x rays using a high‐power frequency‐doubled Nd laser pulse for x‐ray backlighting application. More than 30 laser shots on the Lawrence Livermore National Laboratory JANUS Research Laser system have been studied. The following specific questions are addressed: (a) X‐ray yield dependence on the laser parameters: (i) temporal pulse width and (ii) focusing conditions. (b) X‐ray source size versus target dimensions by using a tungsten wire with various diameters. (c) Influence of background plasma on the x‐ray yield from the wire using 25‐μm wires surrounded by plastic.
The original Lowry method of protein determination has been modified by the addition of sodium dodecyl sulfate in the alkali reagent and an increase in the amount of copper tartrate reagent. These alterations allowed the method to be used with membrane and lipoprotein preparations without prior solubilization or lipid extraction and with samples containing 200 mm sucrose or 2.5 mm EDTA.
To investigate whether adaptation which modifies some acute effects of ozone (O3) exposure can develop in humans, six male volunteers with respiratory hyperreactivity were exposed in a controlled environment chamber to 0.5 ppm O3 2h/day for 4 successive days under conditions stimulating ambient pollution exposures. One subject showed little measurable response, while five showed function decrement on exposure days 1-3 which was largely reversed by day 4. Symptom responses generally paralleled the physiological responses. These results suggest that at least some humans adapt to O3 exposure at concentrations occurring in severe community air pollution episodes, to the extent that obvious acute respiratory effects are prevented. Other adverse effects of O3 may not be prevented by this adaptation.
Groups of Sprague-Dawley rats were exposed to ozone for either 8 or 24 hours a day for 7 consecutive days to evaluate morphologic changes of the respiratory system. Three levels of exposure (0.2, 0.5, and 0.8 p.p.m. of O3) were selected to simulate moderate to severe episodes of oxidant pollution in urban environments. Morphologic evaluation included light, scanning electron, and transmission electron microscopy. Biochemical parameters which were examined included succinate oxidase, glucose-6-phosphate dehydrogenase, and nicotinamide adenine dinucleotide phosphate-cytochrome c reductase activities. The results indicated that (1) exposure to concentrations as low as 0.2 p.p.m. for 7 days induced pulmonary damage; (2) there was a dose-dependent pulmonary response to the three levels of ozone which was quantitated by alterations in biochemical marker enzyme activities and observed morphologically; (3) proportionate differences were not observed in morphologic characteristics of the lesions or detected in biochemical parameters between rats exposed continuously for 7 days and those exposed intermittently for 8 hours a day for 7 consecutive days; (4) alterations in surface height and granularity of the cytoplasmic luminal projection of Clara cells were subtle changes which were dose-dependent, occurring even at the lowest ozone concentration, and best detected by scanning electron microscopy; (5) alveolar macrophage accumulation within proximal alveoli of alveolar ducts was the most readily detectable morphologic indicator of pulmonary damage; and (6) although the brunt of ozone damage was borne by the centriacinar region, there was damage to cilia and increased ciliogenesis occurring in the trachea and larger conducting airways following exposure of 0.5 and 0.8 p.p.m. of ozone.
Five normal human subjects were exposed for 1 h to filtered air (FA) once and to 0.3 ppm O3 on 3 separate days. Bronchoalveolar lavage (BAL) fluid was obtained less than 1 h after FA and either less than 1, 6, or 24 h after O3 exposure. FEV1 was measured before the exposures and the BAL. The first aliquot [proximal airway (PA) sample] was analyzed separately from the pooled Aliquots 2 through 4 [distal airway and alveolar surface (DAAS) sample]. The data from the PA and DAAS samples were then combined to calculate the values that would have been obtained by pooling all BAL washes. FEV1 was significantly (p less than 0.05) decreased 1 h after O3 exposure, but it returned to preexposure values at 6 and 24 h after O3. The percent of neutrophils in the PA sample was significantly elevated at less than 1 h (3.7%) at 6 h (16.5%), and at 24 h (9.2%) after O3. The percent of neutrophils in the DAAS sample and calculated pooled values were significantly elevated at 6 h (4.1 and 7.6%) and at 24 h (5.1 and 5.8%) after O3. These data demonstrate that O3-induced symptoms, FEV1 decrements, and airway neutrophilia follow different time courses and indicate that the pooling of BAL washes may obscure the detection of an O3-induced bronchiolitis. The degree of neutrophilia in the BAL did not correlate with the sensitivity of the individual subjects when measured by acute changes in FEV1, suggesting a dichotomy of pathways that result in O3-induced airway neutrophilia and pulmonary function decrements.
Hydroxymethanesulfonate (HMSA), the bisulfite (HSO3-) adduct of formaldehyde (CH2O), is a common constituent of California acid fogs. HMSA, most stable in a fog pH range of 3 to 5, dissociates at 6.6, the pH of the fluid lining human airways. The dissociation of inhaled HMSA should theoretically generate sulfur dioxide and CH2O, both of which have bronchoconstrictor potential. Thus, we hypothesized that HMSA may have a specific bronchoconstrictor effect independent of its strength as an acid. To determine whether HMSA has such an effect, 19 subjects with mild to moderate asthma were studied using two different protocols. Initially, a mouthpiece study was performed in which 9 subjects, on 2 separate days, inhaled five aerosols containing either sequentially increasing concentrations (0, 30, 100, 300, and 1000 microM) of HMSA in 50 microM sulfuric acid (H2SO4) or 50 microM H2SO4 alone. The subjects inhaled each aerosol for 3 min during tidal breathing at rest. Specific airway resistance (SRaw) was measured before and after each 3-min exposure. There were no significant differences in the mean changes in SRaw among the various aerosol exposures. To confirm this lack of bronchoconstrictor effect of HMSA, we then performed a chamber study in which 10 freely breathing, intermittently exercising subjects were exposed to fog containing either 1 mM HMSA in 5 mM H2SO4 or 5 mM H2SO4 alone for 1 h. SRaw was measured before, during, and at the end of the 1-h exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
The magnitudes of pulmonary responses we previously observed (1) following 6.6-h exposures to 0.12 ppm ozone (O3) suggested that responses would also occur with similar exposures at lower O3 concentrations. The objective of this study was to determine the extent of pulmonary function decrements, respiratory discomfort, and increased airway reactivity to methacholine induced by exposure to O3 below 0.12 ppm. Separate 6.6-h chamber exposures to 0.00, 0.08, 0.10, and 0.12 ppm O3 included six 50-min periods of moderate exercise (VE approximately equal to 39 L/min, HR approximately equal to 115 bpm, and VO2 approximately equal to 1.5 L/min). Each exercise period was followed by 10 min of rest. A 35-min lunch break was included midway through the exposure. Although not intended as an exact simulation, the overall duration, intensity, and metabolic requirements of the exercise performed were representative of a day of moderate to heavy work or play. Preexposure FEV1 averaged 4.39 L, and essentially no change (+0.03 L) occurred with exposure to 0.00 ppm O3. Significant decreases (p less than 0.01) of -0.31, -0.30, and -0.54 L were observed with exposures to 0.08, 0.10, and 0.12 ppm, respectively. The provocative dose of methacholine required to increase airway resistance by 100% (PD100) was 58 cumulative inhalation units (CIU) following exposure to 0.00 ppm and was significantly reduced (p less than 0.01) to 37 CIU at 0.08, 31 CIU at 0.10, and 26 CIU at 0.12 ppm O3; reductions in PD100 are considered indicative of increases in nonspecific airway responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)
The increase in airway responsiveness induced by O3 exposure in dogs is associated with airway epithelial inflammation, as evidenced by an increase in the number of neutrophils (polymorphonuclear leukocytes) found in epithelial biopsies and in bronchoalveolar lavage fluid. We investigated in 10 healthy, human subjects whether O3-induced hyperresponsiveness was similarly associated with airway inflammation by examining changes in the types of cells recovered in bronchoalveolar lavage fluid obtained after exposure to air or to O3 (0.4 or 0.6 ppm). We also measured the concentrations of cyclooxygenase and lipoxygenase metabolites of arachidonic acid in lavage fluid. We measured airway responsiveness to inhaled methacholine aerosol before and after each exposure and performed bronchoalveolar lavage 3 h later. We found more neutrophils in the lavage fluid from O3-exposed subjects, especially in those in whom O3 exposure produced an increase in airway responsiveness. We also found significant increases in the concentrations of prostaglandins E2, F2 alpha, and thromboxane B2 in lavage fluid from O3-exposed subjects. These results show that in human subjects O3-induced hyperresponsiveness to methacholine is associated with an influx of neutrophils into the airways and with changes in the levels of some cyclooxygenase metabolites of arachidonic acid.
A detailed comparison of literature-reported averaged decrements in pulmonary function of normal subjects exposed to O3 has been undertaken. The data base was formed by including data published during the past 20 yr from studies that reported at least one of the pulmonary function variables (forced vital capacity, forced expiratory volume at 1 s, mean forced expiratory flow between 25 and 75% of forced vital capacity, and airway resistance) acquired at 2 h of exposures utilizing either original or modified Bates-Hazucha (intermittent exercise) protocol and that satisfied selection criteria. The final set of data (24 studies involving 299 subjects) was divided by ventilation rate (exercise loads) into four categories: light, moderate, high, and very high ventilation level. For each pulmonary function variable and ventilation level a quadratic function has been fitted to the data using regression procedures. The curve parameter estimates have been computed, tabulated, and statistically evaluated. The slope (quadratic coefficient) for each variable within a group and almost all variables between groups were significantly different from zero and from each other at P less than or equal to 0.0001.
ALL assay procedures which do not rely on the direct detection of a specific property of the unknown substance must depend on the reaction of an unknown with a reagent to give a product which can then be assayed. The product can be estimated directly or indirectly (for example, as a result of a further reaction). If the unknown is regenerated after the primary reaction it may then react with more reagent and a cycling assay is established. The advantage of such a system is that one molecule of the unknown gives rise to several molecules of product with a consequent increase in sensitivity. The reagent can be as diverse as a dye, neutron irradiation, an enzyme substrate or an antibody. Adequate assay systems must be shown to have suitable specificity, sensitivity, precision, range and convenience. In order to obtain maximum sensitivity and precision: (1) all the unknown should be reacted at least once and preferably several times; (2) the amount of product should be assayed by a procedure which gives a low background and shows changes in direct proportion to the change in product concentration; (3) the property measured should be capable of detection at very low concentrations of the product. The use of one or more cycling reactions is one well recognized way of achieving suitable amplification (compare the assay of metabolic intermediates and enzymes).
Because minimal data are available regarding the pulmonary effects of ozone (O3) at levels less than 0.27 ppm, six groups of healthy young males were exposed for 2.5 h to one of the following O3 concentrations: 0.0, 0.12, 0.18, 0.24, 0.30, or 0.40 ppm. Fifteen-minute periods of rest and exercise (65 l/min minute ventilation) were alternated during the first 2 h of exposure. Coughing was observed at all levels of O3 exposure. Small changes in forced-expiratory spirometric variables [forced vital capacity (FVC), forced expiratory volume in 1 s, and mean expiratory flow rate between 25 and 75% FVC] were observed at 0.12 and 0.18 ppm O3, and larger changes were found at O3 levels greater than or equal to 0.24 ppm. Changes in tidal volume and respiratory frequency during exercise, specific airway resistance, the presence of pain on deep inspiration, and shortness of breath occurred at O3 levels greater than or equal to 0.24 ppm. In conclusion, pulmonary effects of O3 were observed at levels much lower than that for which these effects have been previously described. Stimulation of airway receptors is probably the mechanism responsible for the majority of observed changes; however, the existence of a second mechanism of action is postulated.
Repeated ozone exposure induces an adaptative response whereby subsequent ozone exposure induces little or no pulmonary function change. The time course of the adaptation and the persistence of this adaptation was determined in 24 subjects. Subjects were studied for 125 min while they exercised intermittently. They were exposed to filtered air for 1 day and then in the next week for 5 consecutive days to 0.5 ppm ozone. After the fifth day, subjects were randomly assigned to return for one more ozone exposure at 1, 2, or 3 wk. The greatest decrement in FEV1 occurred on the second day of exposure. The number of consecutive ozone exposures required to produce adaptation varied from 2 to 5 days. Persistence of adaptation in ozone-sensitive subjects (initial decrease in FEV1 greater than 10%) showed marked individual variability, but the duration of adaptation was shortest for the more sensitive subjects. Adaptation, on the average, lasted for less than 2 wk, being as short as 7 days and as long as 20 days. We concluded that more sensitive subjects required more daily sequential exposures in order to adapt.
The attenuating influence of a pre-exposure of rats to a low concentration of ozone (O3) for 7 days on a subsequent O3 challenge was investigated. Effects of O3 were quantified by measuring indicators of lung permeability and inflammation in bronchoalveolar lavage fluid. The results suggest that pre-exposure to relatively low levels of O3 produces a diminished permeability response in lower airways of rats upon a following challenge with a higher level of O3. Extrapolated to human exposure situations, these data suggest that health effect evaluation of repeated exposure periods of enhanced O3 levels is rather complex and needs further investigation.
Nitric acid (HNO3) is the most prevalent acid air pollutant in the western United States and has the potential to cause adverse respiratory effects through both acidification and oxidation reactions. To study this potential, we measured physiologic (specific airway resistance, SRaw, FEV1, and FVC) and bronchoalveolar lavage (total and differential cell counts, LDH, fibronectin, and total protein) end points in a group of 10 healthy, athletic subjects who were exposed to 500 micrograms/m3 of HNO3 gas or filtered air for 4 h during moderate exercise (ventilatory rate, 40 L/min) and underwent bronchoscopy 18 h later. Under an identical protocol, 10 healthy subjects were exposed to 500 micrograms/m3 of HNO3 gas plus 0.20 ppm ozone (O3) or 0.20 ppm O3 alone to determine if HNO3 might enhance the toxicity of O3. In addition to bronchoalveolar lavage (BAL), we employed the techniques of isolated left mainstem bronchial lavage and bronchial biopsy to determine if proximal airway injury was caused by pollutant exposure and whether there was any correlation with the degree of distal lung injury as assessed by BAL. We found no significant differences in pulmonary function tests or in the cellular or biochemical constituents in either the BAL or the left mainstem lavage fluids between the HNO3 and the air exposures. Similarly, there were no differences in these end points between the HNO3/O3 and the O3 exposures. Furthermore, there were no significant differences in the bronchial biopsy specimens between the HNO3 and air exposures or between the HNO3/O3 and O3 exposures.(ABSTRACT TRUNCATED AT 250 WORDS)
Ozone (O3) is a major constituent of urban air pollution. The acute effects of the inhalation of O3 at ambient or near-ambient concentrations on bronchoalveolar lavage (BAL) end points consistent with a distal lung inflammatory response have been well documented in human subjects. Animal toxicologic studies have shown that the airway is also a major site of O3-induced injury and inflammation. To date, no studies have confirmed this finding in human subjects. Effects of O3 on the proximal airways are not adequately studied by BAL, which is primarily influenced by events occurring in the terminal bronchioles and alveoli. We hypothesized that O3 causes injury and inflammation in the airways in addition to that previously documented to occur in the distal lung. We performed isolated lavage of the left mainstem bronchus and forceps biopsy of the bronchial mucosa in a group of 14 healthy, athletic subjects 18 h after exposure to 0.20 ppm O3 for 4 h during moderate exercise in order to assess this possibility. We followed an identical protocol in a similar group of 12 subjects exposed to filtered air. The mean (SD) total cell count and the lactate dehydrogenase (LDH) concentration in the isolated airway lavage were significantly greater after O3 than after air, 13.9 (20.5) versus 4.9 (5.4) cells/ml x 10(4) and 18.9 (11.2) versus 9.6 (9.0) U/L, respectively. Morphometry (2,070 neutrophils/cm2 of tissue for O3 and 330 neutrophils/cm2 of tissue for air) demonstrated that O3 exposure induced an acute inflammatory cell influx into the airway.(ABSTRACT TRUNCATED AT 250 WORDS)
In order to test the hypothesis that changes in lung function induced by ozone (O3) are correlated with cellular and biochemical indices of respiratory tract injury/inflammation, we exposed 20 healthy subjects, on separate days, to O3 (0.2 ppm) and filtered air for 4 h during exercise. Symptom questionnaires were administered before and after exposure, and pulmonary function tests (FEV1, FVC, and SRaw) were performed before, during, and immediately after each exposure. Fiberoptic bronchoscopy, with isolated left main bronchus proximal airway lavage (PAL) and bronchoalveolar lavage (BAL; bronchial fraction, the first 10 ml of fluid recovered) of the right middle lobe, was performed 18 h after each exposure. The PAL, bronchial fraction, and BAL fluids were analyzed for the following end points: total and differential cell counts, and total protein, fibronectin, interleukin-8 (IL-8), and granulocyte-macrophage colony-stimulating factor (GM-CSF) concentrations. The study population was divided into two groups, least-sensitive (n = 12; mean O3-induced change in FEV1 = -7.0%) and most-sensitive (n = 8; mean O3-induced change in FEV1 = -36.0%). We found a significant O3 effect on SRaw (p<0.001) and lower respiratory symptoms (p<0.001) for all subjects combined, but no significant differences between the least- and most-sensitive groups. Ozone exposure increased significantly percent neutrophils in PAL (p=0.01); percent neutrophils, total protein, and IL-8 in bronchial fraction (p<0.001, p<0.001, and p<0.01, respectively); and percent neutrophils, total protein, fibronectin, and GM-CSF in BAL (p<0.001, p<0.001, p<0.01, p=0.05, respectively) for all subjects combined; there were no significant differences, however, between least- and most-sensitive groups. Our results indicate that levels of O3-induced symptoms and respiratory tract injury/inflammation were not correlated with the magnitude of decrements in FEV1 and FVC.