Geospatial analysis of individual-based Parkinson's disease data supports a link with air pollution: A case-control study.

BACKGROUND: The etiology of Parkinson's disease (PD) remains unknown. To approach the issue of PD's risk factors from a new perspective, we hypothesized that coupling the geographic distribution of PD with spatial statistics may provide new insights into environmental epidemiology research. The aim of this case-control study was to examine the spatial dependence of PD prevalence in the Canton of Geneva, Switzerland (population = 474,211). METHODS: PD cases were identified through Geneva University Hospitals, private neurologists and nursing homes medical records (n = 1115). Controls derived from a population-based study (n = 12,614) and a comprehensive population census dataset (n = 237,771). All individuals were geographically localized based on their place of residence. Spatial Getis-Ord Gi* statistics were used to identify clusters of high versus low disease prevalence. Confounder-adjustment was performed for age, sex, nationality and income. Tukey's honestly significant difference was used to determine whether nitrogen dioxide and particulate matters PM10 concentrations were different within PD hotspots, coldspots or neutral areas. RESULTS: Confounder-adjustment greatly reduced greatly the spatial association. Characteristics of the geographic space influenced PD prevalence in 6% of patients. PD hotspots were concentrated in the urban centre. There was a significant difference in mean annual nitrogen dioxide and PM10 levels (+3.6 µg/m3 [p < 0.001] and +0.63 µg/m3 [p < 0.001] respectively) between PD hotspots and coldspots. CONCLUSION: PD prevalence exhibited a spatial dependence for a small but significant proportion of patients. A positive association was detected between PD clusters and air pollution. Our data emphasize the multifactorial nature of PD and support a link between PD and air pollution.

Long-term exposure to PM10 and NO2 in relation to lung function and imaging phenotypes in a COPD cohort.

BACKGROUND: Ambient air pollution can contribute to the development and exacerbation of COPD. However, the influence of air pollution on objective COPD phenotypes, especially from imaging, is not well studied. We investigated the influence of long-term exposure to air pollution on lung function and quantitative imaging measurements in a Korean cohort of participants with and without COPD diagnosis. METHODS: Study participants (N = 457 including 296 COPD cases) were obtained from the COPD in Dusty Areas (CODA) cohort. Annual average concentrations of particulate matter less than or equal to 10 µm in diameter (PM10) and nitrogen dioxide (NO2) were estimated at the participants' residential addresses using a spatial air pollution prediction model. All the participants underwent volumetric computerized tomography (CT) and spirometry measurements and completed survey questionnaires. We examined the associations of PM10 and NO2 with FVC, FEV1, emphysema index, and wall area percent, using linear regression models adjusting for age, gender, education, smoking, height, weight, and COPD medication. RESULTS: The age of study participants averaged 71.7 years. An interquartile range difference in annual PM10 exposure of 4.4 µg/m3 was associated with 0.13 L lower FVC (95% confidence interval (CI), - 0.22- -0.05, p = 0.003). Emphysema index (mean = 6.36) was higher by 1.13 (95% CI, 0.25-2.02, p = 0.012) and wall area percent (mean = 68.8) was higher by 1.04 (95% CI, 0.27-1.80, p = 0.008). Associations with imaging phenotypes  were not observed with NO2. CONCLUSIONS: Long-term exposure to PM10 correlated with both lung function and COPD-relevant imaging phenotypes in a Korean cohort.

[ROLE OF MAST CELLS IN BRONCHIAL CONTRACTION IN NONALLERGIC OBSTRUCTIVE LUNG PATHOLOGY].

In model of chronic obstructive pulmonary disease induced in rats by 60-day intermittent exposure to nitrogen dioxide mast cells participation in the mechanism of bronchial smooth muscle contractile activity patterns was evaluated. Since the 31st day, one group of rats was inhaled with sodium cromoglycate every day before the nitrogen dioxide exposure to stabilize the mast cell membrane. The other group (control) hasn't been treated. Isometric contraction of the bronchial isolated preparations in response to nerve or smooth muscle stimulation were determined. Inhibition of mast cell degranulation and the release of endogenous histamine by stabilizing cell membranes prevented the development of bronchial smooth muscle hyperactivity caused by prolonged inhalation of nitrogen dioxide. It is believed that a mechanism to increase the contractile activity of the bronchial wall smooth muscles is mediated by activation of the transmembrane adenosine receptor in resident mast cells, leading to their partial degranulation with release of histamine, acting on the histamine Hl-receptors with the launch of reflex pathways through intramural ganglion neurons.

[ANTIINFLAMMATORY AND REGENERATIVE EFFECT OF PEPTIDE THERAPY IN THE MODEL OF OBSTRUCTIVE LUNG PATHOLOGY].

The effect of the tetrapeptide bronchogen on the structural and functional state of the bronchial epithelium and inflammatory activity in the lungs was studied in the chronic obstructive pulmonary disease (COPD) model, created in rats by a 60-day intermittent exposure to nitrogen dioxide. The cell composition and cytokine-enzyme profile of bronchoalveolar lavage fluid (BALF), the content of secretory immunoglobulin A and surfactant protein B in BALF were determined. Following the course of peptide treatment the decreased activity of neutrophilic inflammation with the normalization of cellular composition and profile of pro-inflammatory cytokines and enzymes in the bronchoalveolar space was observed. The structure of bronchial epithelium, disturbed during formation of COPD model, was restored and accompanied by restoration of its functional activity as evidenced by an increase of secretory immunoglobulin A (local immunity marker) and surfactant protein B, responsible for reducing the alveolar surface tension.

Environmental NO2 and CO Exposure: Ignored Factors Associated with Uremic Pruritus in Patients Undergoing Hemodialysis.

Uremic pruritus (UP), also known as chronic kidney disease-associated pruritus, is a common and disabling symptom in patients undergoing maintenance hemodialysis (MHD). The pathogenesis of UP is multifactorial and poorly understood. Outdoor air pollution has well-known effects on the health of patients with allergic diseases through an inflammatory process. Air pollution-induced inflammation could occur in the skin and aggravate skin symptoms such as pruritus or impair epidermal barrier function. To assess the role of air pollutants, and other clinical variables on uremic pruritus (UP) in HD patients, we recruited 866 patients on maintenance HD. We analyzed the following variables for association with UP: average previous 12-month and 24-month background concentrations for nitrogen dioxide (NO2) and carbon monoxide (CO), and suspended particulate matter of <2.5 µm (PM2.5). In a multivariate logistic regression, hemodialysis duration, serum ferritin levels, low-density lipoprotein levels, and environmental NO2/CO levels were positively associated with UP, and serum albumin levels were negatively associated with UP. This cross-sectional study showed that air pollutants such as NO2 and CO might be associated with UP in patients with MHD.

[EFFECT OF MAST CELL DEGRANULATION BLOCKADE ON THE INFLAMMATION OUTCOME IN THE MODEL OF OBSTRUCTIVE LUNG PATHOLOGY].

Effect of mast cell degranulation blockade on the inflammatory response and character of the lung tissue structure-functional changes were evaluated in the chronic obstructive pulmonary disease model produced in rats by 60-day intermittent exposure to nitrogen dioxide. The membrane stabilizer sodium cromoglicate was used to blockade of mast cell degranulation. Lung tissue sections were stained with toluidine blue to identify mast cells. Bronchoalveolar lavage fluid (BALF) cytogram was determined. The levels of mast cell tryptase and chymase, proinflammatory cytokine TNF-α, surfactant protein B were measured in BALF. Suppression of mast cell degranulation prevented the release of proteases in the bronchoalveolar space and reduced activity of the inflammatory process. The influx of inflammatory cells and TNF-α concentration decreased. There was no interstitial inflammatory infiltration. Bronchoalveolar epithelium structure was recovered that is the basis of its functional usefulness. The results confirm the active involvement of mast cells in the development of the inflammatory process in obstructive pulmonary diseases and allow us to consider them as a possible therapeutic target.

Exposure to traffic-related air pollution during physical activity and acute changes in blood pressure, autonomic and micro-vascular function in women: a cross-over study.

BACKGROUND: Traffic-related air pollution may contribute to cardiovascular morbidity. In urban areas, exposures during physical activity are of interest owing to increased breathing rates and close proximity to vehicle emissions. METHODS: We conducted a cross-over study among 53 healthy non-smoking women in Montreal, Canada during the summer of 2013. Women were exposed to traffic pollutants for 2-hours on three separate occasions during cycling on high and low-traffic routes as well as indoors. Personal air pollution exposures (PM(2.5), ultrafine particles (UFP), black carbon, NO2, and O3) were evaluated along each route and linear mixed-effects models with random subject intercepts were used to estimate the impact of air pollutants on acute changes in blood pressure, heart rate variability, and micro-vascular function in the hours immediately following exposure. Single and multi-pollutant models were examined and potential effect modification by mean regional air pollution concentrations (PM(2.5), NO2, and O3) was explored for the 24-hour and 5-day periods preceding exposure. RESULTS: In total, 143 exposure routes were completed. Each interquartile increase (10,850/cm³) in UFP exposure was associated with a 4.91% (95% CI: -9.31, -0.512) decrease in reactive hyperemia index (a measure of micro-vascular function) and each 24 ppb increase in O3 exposure corresponded to a 2.49% (95% CI: 0.141, 4.84) increase in systolic blood pressure and a 3.26% (95% CI: 0.0117, 6.51) increase in diastolic blood pressure 3-hours after exposure. Personal exposure to PM(2.5) was associated with decreases in HRV measures reflecting parasympathetic modulation of the heart and regional PM(2.5) concentrations modified these relationships (p < 0.05). In particular, stronger inverse associations were observed when regional PM(2.5) was higher on the days prior to the study period. Regional PM(2.5) also modified the impact of personal O3 on the standard deviation of normal to normal intervals (SDNN) (p < 0.05): a significant inverse relationship was observed when regional PM(2.5) was low prior to study periods and a significant positive relationship was observed when regional PM(2.5) was high. CONCLUSION: Exposure to traffic pollution may contribute to acute changes in blood pressure, autonomic and micro-vascular function in women. Regional air pollution concentrations may modify the impact of these exposures on autonomic function.

A dynamic system for single and repeated exposure of airway epithelial cells to gaseous pollutants.

In vitro models are promising approaches to investigate the adverse effects and the mode of action of air pollutants on the respiratory tract. We designed a dynamic system that allows the single or repeated exposure of cultured cells to two major indoor air gaseous pollutants, formaldehyde (HCHO) and nitrogen dioxide (NO2), alone or as a mixture. In this system, the Calu-3 human bronchial epithelial cell line was exposed at the air-liquid interface (ALI) or submerged by culture medium to synthetic air or to target concentrations of HCHO and/or NO2 once or on 4 consecutive days before assessment of cell viability and necrosis, IL-6 and IL-8 release and trans-epithelial electrical resistance. Our data showed that whereas the ALI method can be used for single short-term exposures only, the submerged method provides the possibility to expose Calu-3 cells in a repeated manner. As well, we found that repeated exposures of the cells to HCHO and NO2 at concentrations that can be found indoors triggered a significant decrease in cell metabolism and an increase in IL-8 release that were not evoked by a single exposure. Thus, our work highlights the fact that the development of systems and methods that allow repeated exposures of cultured cells to gaseous compounds in mixtures is of major interest to evaluate the impact of air pollution on the respiratory tract.

Wildland smoke exposure values and exhaled breath indicators in firefighters.

Smoke from forest fires contains significant amounts of gaseous and particulate pollutants. Firefighters exposed to wildland fire smoke can suffer from several acute and chronic adverse health effects. Consequently, exposure data are of vital importance for the establishment of cause/effect relationships between exposure to smoke and firefighter health effects. The aims of this study were to (1) characterize the relationship between wildland smoke exposure and medical parameters and (2) identify health effects pertinent to wildland forest fire smoke exposure. In this study, firefighter exposure levels of carbon monoxide (CO), nitrogen dioxide (NO2), and volatile organic compounds (VOC) were measured in wildfires during three fire seasons in Portugal. Personal monitoring devices were used to measure exposure. Firefighters were also tested for exhaled nitric oxide (eNO) and CO before and after their firefighting activities. Data indicated that exposure levels during firefighting activities were beyond limits recommended by the Occupational Exposure Standard (OES) values. Medical tests conducted on the firefighters also indicated a considerable effect on measured medical parameters, with a significant increase in CO and decrease in NO in exhaled air of majority of the firefighters.

Experimental modelling of chronic obstructive pulmonary disease.

A method for experimental reproduction of stages of chronic obstructive pulmonary disease formation (from acute inflammation to bronchopulmonary tissue restructuring characteristic of this disease) is presented. Lung injury and inflammation were induced by nitrogen dioxide. Hyperplasia and hypersecretion of goblet cells, squamous cell metaplasia of the ciliary epithelium, emphysema, and focal fibrosis served as the morphological substrate for the formation of bronchial obstruction. The adequacy of the model is confirmed by signs characteristic of chronic obstructive pulmonary disease: hyperexpression of CD3 lymphocytes in the bronchial wall and parenchyma, manifold increased production of TNFα and TGFß, high concentrations of circulating pathogenic immune complexes. Persistence of the structural and functional shifts throughout 6 months after exposure to nitrogen dioxide indicated a chronic course of the resultant pathological process.

[Determination of circulation disturbance in the rat lungs in modelling of chronic obstructive disease].

Development of chronic obstructive pulmonary disease (COPD) involves not only the bronchial and respiratory areas of the lungs, but also the system of pulmonary circulation, which begins with the defeat of capillary blood flow. One of radiological methods of studying lung microcirculatory functions is perfusion scintigraphy. We designed the technique of radiological examination and identified its abilities in determination of the role of vascular dysfunctions in experimental model of development of COPD. We assessed the results of pharmacological agents that affect the microcirculatory bed of the lungs and smooth muscles of pulmonary arteries in rats. Studies have shown the promise of the possibility of using the drug sulodexide for studying impaired endothelial function in clinical practice.

[Establishment of acute pulmonary edema model induced by high concentrations of nitrogen dioxide in rats].

OBJECTIVE: To establish the rats model of acute pulmonary edema induced by inhalation of high concentrations of nitrogen dioxide (NO2). METHODS: 38 SD rats were divided into the experimental group (n = 30) and the control group (n = 8). 30 rats in the experimental group were exposed to (6747.47 ± 25.24) mg/m(3) NO2 in the exposure system. At the time point of 6, 12, 18, 24 h, chest X-ray examination was taken for the experimental group. And at each time point, 6 rats were sacrificed after taking blood samples. After sacrificing, the lung of rats was taken for pathological examination and calculated lung wet/dry weight ratio. Erythrocyte superoxide dismutase (SOD) activity and plasma atrial natriuretic peptide (ANP) concentration of blood samples were detected. RESULTS: Acute pulmonary edema was successfully induced by exposure to NO2 in 30 rats within 24 hours. There were some cloudy shadows without clear edge on the chest X-ray. To the time point of 12 hours, shadows combined with each other, and to the time point of 18 hours, the whole lung became "white" on the X-ray. The situation stabilized but not improved at the time point of 24 hours. HE staining of the lung tissue showed that to the time point of 6 hours, the alveolar gap increased and small amount of eosinophilic liquid leaked into alveolar. To the time point of 12 hours, alveolar combined with each other and eosinophilic liquid increased in amount. To the time point of 18 hours, the whole alveolar was filled with eosinophilic liquid and the situation stabilized till the time point of 24 hours. Wet/dry weight ratio of the experimental group at each time point were 5.6 ± 0.20, 6.89 ± 0.25, 8.03 ± 0.47, 7.81 ± 0.45. There was significant difference compared with the control group which was 4.72 ± 0.06 (P < 0.01). There was statistical difference between 12, 18, 24 h and 6 h time points (P < 0.01). Moreover, statistical difference was observed between 18, 24 h and 12 h time points for wet/dry weight ratio (P < 0.01). The erythrocyte SOD activity reduced significantly. Compared with the control group, there was a statistical difference (P < 0.01) at each time point. After exposure of 18 and 24 hours, plasma ANP concentration (136.66 ± 35.37) and (134.10 ± 60.41) ng/ml respectively, which were higher than (31.31 ± 13.06) ng/ml of control group and (34.71 ± 13.42) ng/ml of 6 hours time point and (47.98 ± 7.86) ng/ml. The differences were significant (P < 0.01). CONCLUSION: High concentrations of NO2 can induce acute pulmonary edema model successfully in SD rats.

Social factors associated with nitrogen dioxide (NO2) exposure during pregnancy: the INMA-Valencia project in Spain.

Numerous studies have focused on the effects of exposure to air pollution on health; however, certain subsets of the population tend to be more exposed to such pollutants depending on their social or demographic characteristics. In addition, exposure to toxicants during pregnancy may play a deleterious role in fetal development as fetuses are especially vulnerable to external insults. The present study was carried out within the framework of the INMA (Infancia y Medio Ambiente or Childhood and the Environment) multicenter cohort study with the objective of identifying the social, demographic, and life-style factors associated with nitrogen dioxide (NO(2)) exposure in the subjects in the cohort. The study comprised 785 pregnant women who formed part of the INMA cohort in Valencia, Spain. Outdoor levels of NO(2) were measured at 93 sampling sites spread over the study area during four different sampling periods lasting 7 days each. Multiple regression models were used for mapping outdoor NO(2) throughout the area. Individual exposure was assigned as: 1) the estimated outdoor NO(2) levels at home, and 2) the average of estimated outdoor NO(2) levels at home and work, weighted according to the time spent in each environment. The subjects' socio-demographic and life-style information was obtained through a questionnaire. In the multiple linear analyses, the outdoor NO(2) levels assigned to each home were taken to be the dependent variable. Other variables included in the model were: age, country of origin, smoking during pregnancy, parity, season of the year, and social class. These same variables remained in the model when the dependent variable was changed to the NO(2) levels adjusted for the subjects' time-activity patterns. We found that younger women, those coming from Latin American countries, and those belonging to the lower social strata were exposed to higher NO(2) levels, both as measured outside their homes as well as when time-activity patterns were taken into account. These subgroups also have a higher probability of being exposed to NO(2) levels over 40 µg/m(3), which is the annual limit for maximum safe exposure, as established by European Directive 2008/50/EC.

Absorption of inhaled NO(2).

Nitrogen dioxide (NO(2)), a sparingly water-soluble pi-radical gas, is a criteria air pollutant that induces adverse health effects. How is inhaled NO(2)(g) incorporated into the fluid microfilms lining respiratory airways remains an open issue because its exceedingly small uptake coefficient (gamma approximately 10(-7)-10(-8)) limits physical dissolution on neat water. Here, we investigate whether the biological antioxidants present in these fluids enhance NO(2)(g) dissolution by monitoring the surface of aqueous ascorbate, urate, and glutathione microdroplets exposed to NO(2)(g) for approximately 1 ms via online thermospray ionization mass spectrometry. We found that antioxidants catalyze the hydrolytic disproportionation of NO(2)(g), 2NO(2)(g) + H(2)O(l) = NO(3)(-)(aq) + H(+)(aq) + HONO, but are not consumed in the process. Because this function will be largely performed by chloride, the major anion in airway lining fluids, we infer that inhaled NO(2)(g) delivers H(+), HONO, and NO(3)(-) as primary transducers of toxic action without antioxidant participation.

Inhalational lung injury due to nitrogen dioxide: high-resolution computed tomography findings in 3 patients.

Chest radiographic and high-resolution computed tomography findings of 3 patients with inhalational lung injury due to nitrogen dioxide were reported. Chest radiographs showed ill-defined round opacities which tended to coalesce in both lung with inner lung predominance. High-resolution computed tomography showed ground-glass attenuation and ill-defined centrilobular nodules distributed predominantly in the inner and middle lung zones. One patient showed progression of opacities, which corresponded to the findings of acute respiratory distress syndrome.

Nitrogen dioxide promotes allergic sensitization to inhaled antigen.

Allergen sensitization and allergic airway disease are likely to come about through the inhalation of Ag with immunostimulatory molecules. However, environmental pollutants, including nitrogen dioxide (NO2), may promote adaptive immune responses to innocuous Ags that are not by themselves immunostimulatory. We tested in C57BL/6 mice whether exposure to NO2, followed by inhalation of the innocuous protein Ag, OVA, would result in allergen sensitization and the subsequent development of allergic airway disease. Following challenge with aerosolized OVA alone, mice previously exposed via inhalation to NO2 and OVA developed eosinophilic inflammation and mucus cell metaplasia in the lungs, as well as OVA-specific IgE and IgG1, and Th2-type cytokine responses. One hour of exposure to 10 parts per million NO2 increased bronchoalveolar lavage fluid levels of total protein, lactate dehydrogenase activity, and heat shock protein 70; promoted the activation of NF-kappaB by airway epithelial cells; and stimulated the subsequent allergic response to Ag challenge. Furthermore, features of allergic airway disease were not induced in allergen-challenged TLR2-/- and MyD88-/- mice exposed to NO2 and aerosolized OVA during sensitization. These findings offer a mechanism whereby allergen sensitization and asthma may result under conditions of high ambient or endogenous NO2 levels.

[Development of a nitric oxide inhaling equipment cooperated with the ventilator synchronously].

A nitric oxide inhaling equipment cooperated with the ventilator synchronously, is introduced in this paper. This equipment monitors the inspiratory flow of the ventilator by a gas flow meter, and works out the flow value of NO on the therapeutic condition using the formula of gas dilution. Then its mass flow controller controls the flow of NO and delivers it to the respiratory circuit. At the same time, the concentrations of NO and NO2 are detected by the electrochemical NO/NO2 sensors before the therapeutic gas enters into the patient. The experimental result shows that this equipment can work with the ventilator in-phase periodically, the volume of E/(I+E) NO be saved, and the output of NO2 < or = 0.7 x 10(-6). Thus the equipment not only has realized the intellectual monitoring and gas-dispensing, but also has improved the precision of inhaled NO concentration with a better reliability and security during the therapy.

Nitrogen dioxide enhances allergic airway inflammation and hyperresponsiveness in the mouse.

In addition to being an air pollutant, NO2 is a potent inflammatory oxidant generated endogenously by myeloperoxidase and eosinophil peroxidase. In these studies, we sought to determine the effects of NO2 exposure on mice with ongoing allergic airway disease pathology. Mice were sensitized and challenged with the antigen ovalbumin (OVA) to generate airway inflammation and subsequently exposed to 5 or 25 ppm NO2 for 3 days or 5 days followed by a 20-day recovery period. Whereas 5 ppm NO2 elicited no pathological changes, inhalation of 25 ppm NO2 alone induced acute lung injury, which peaked after 3 days and was characterized by increases in protein, LDH, and neutrophils recovered by BAL, as well as lesions within terminal bronchioles. Importantly, 25 ppm NO2 was also sufficient to cause AHR in mice, a cardinal feature of asthma. The inflammatory changes were ameliorated after 5 days of inhalation and completely resolved after 20 days of recovery after the 5-day inhalation. In contrast, in mice immunized and challenged with OVA, inhalation of 25 ppm NO2 caused a marked augmentation of eosinophilic inflammation and terminal bronchiolar lesions, which extended significantly into the alveoli. Moreover, 20 days postcessation of the 5-day 25 ppm NO2 inhalation regimen, eosinophilic and neutrophilic inflammation, pulmonary lesions, and AHR were still present in mice immunized and challenged with OVA. Collectively, these observations suggest an important role for NO2 in airway pathologies associated with asthma, both in modulation of degree and duration of inflammatory response, as well as in induction of AHR.

Investigating the dose-response relation between air pollution and total mortality in the APHEA-2 multicity project.

BACKGROUND: Several recent studies have reported significant health effects of air pollution even at low levels of air pollutants, but in most of these studies linear non-threshold relations were assumed. AIMS: To investigate the NO2 mortality dose-response association in nine cities participating in the APHEA-2 project using two different methods: the meta-smooth and the cubic spline method. METHODS: The meta-smooth method developed by Schwartz and Zanobetti is based on combining individual city non-parametric smooth curves; the cubic spline method developed within the APHEA-2 project combines individual city estimates of cubic spline shaped dose-response relations. The meta-smooth method is easier and faster to implement, but the cubic spline method is more flexible for further investigation of possible heterogeneity in the dose-response curves among cities. RESULTS: In the range of the pollutant common to all cities the two methods gave similar and comparable curves. Using the cubic spline method it was found that smoking prevalence acts as an effect modifier with larger NO2 effects on mortality at lower smoking prevalence. CONCLUSIONS: The NO2-mortality association in the cities included in the present analysis, could be adequately estimated using the linear model. However, investigation of the city specific dose-response curves should precede the application of linear models.

Shift toward an alternatively activated macrophage response in lungs of NO2-exposed rats.

Inflammatory mechanisms are thought to play an important role in the pathogenesis of acute and chronic obstructive pulmonary diseases. In a rat inhalation model using continuous exposure to 10 ppm nitrogen dioxide for 1, 3, and 20 d, we investigated the inflammatory response with particular focus on the activation state of alveolar macrophages. Whereas the number of inflammatory cells and total protein concentration were increased in the bronchoalveolar lavage (BAL), the amount of the proinflammatory cytokine tumor necrosis factor-alpha was markedly reduced with increasing exposure time. In contrast, interleukin (IL)-10 and IL-6 were found at elevated levels and intracellular amounts of suppressor of cytokine signaling-3 protein increased in BAL cells. Upon in vitro lipopolysaccharide stimulation, BAL cells revealed reduced capability to produce the proinflammatory mediators tumor necrosis factor-alpha, IL-1 beta, and nitric oxide, but showed markedly increased transcription and protein release for IL-10. In addition, elevated levels of IL-6, scavenger receptor B, and suppressor of cytokine signaling-3 mRNA were detected in BAL cells from exposed animals. Analyses of highly purified alveolar macrophages indicated that changes in the activation state of these cells were responsible for the observed effects. In conclusion, a priming toward development of the alternatively activated macrophage phenotype occurred in the lungs of rats following nitrogen dioxide inhalation.