Human exposure to diesel exhaust induces CYP1A1 expression and AhR activation without a coordinated antioxidant response.

BACKGROUND: Diesel exhaust (DE) induces neutrophilia and lymphocytosis in experimentally exposed humans. These responses occur in parallel to nuclear migration of NF-κB and c-Jun, activation of mitogen activated protein kinases and increased production of inflammatory mediators. There remains uncertainty regarding the impact of DE on endogenous antioxidant and xenobiotic defences, mediated by nuclear factor erythroid 2-related factor 2 (Nrf2) and the aryl hydrocarbon receptor (AhR) respectively, and the extent to which cellular antioxidant adaptations protect against the adverse effects of DE. METHODS: Using immunohistochemistry we investigated the nuclear localization of Nrf2 and AhR in the epithelium of endobronchial mucosal biopsies from healthy subjects six-hours post exposure to DE (PM10, 300 µg/m3) versus post-filtered air in a randomized double blind study, as a marker of activation. Cytoplasmic expression of cytochrome P450s, family 1, subfamily A, polypeptide 1 (CYP1A1) and subfamily B, Polypeptide 1 (CYP1B1) were examined to confirm AhR activation; with the expression of aldo-keto reductases (AKR1A1, AKR1C1 and AKR1C3), epoxide hydrolase and NAD(P)H dehydrogenase quinone 1 (NQO1) also quantified. Inflammatory and oxidative stress markers were examined to contextualize the responses observed. RESULTS: DE exposure caused an influx of neutrophils to the bronchial airway surface (p = 0.013), as well as increased bronchial submucosal neutrophil (p < 0.001), lymphocyte (p = 0.007) and mast cell (p = 0.002) numbers. In addition, DE exposure enhanced the nuclear translocation of the AhR and increased the CYP1A1 expression in the bronchial epithelium (p = 0.001 and p = 0.028, respectively). Nuclear translocation of AhR was also increased in the submucosal leukocytes (p < 0.001). Epithelial nuclear AhR expression was negatively associated with bronchial submucosal CD3 numbers post DE (r = -0.706, p = 0.002). In contrast, DE did not increase nuclear translocation of Nrf2 and was associated with decreased NQO1 in bronchial epithelial cells (p = 0.02), without affecting CYP1B1, aldo-keto reductases, or epoxide hydrolase protein expression. CONCLUSION: These in vivo human data confirm earlier cell and animal-based observations of the induction of the AhR and CYP1A1 by diesel exhaust. The induction of phase I xenobiotic response occurred in the absence of the induction of antioxidant or phase II xenobiotic defences at the investigated time point 6 h post-exposures. This suggests DE-associated compounds, such as polycyclic aromatic hydrocarbons (PAHs), may induce acute inflammation and alter detoxification enzymes without concomitant protective cellular adaptations in human airways.

Cytokine mRNA profile of alveolar T lymphocytes and macrophages in patients with systemic sclerosis suggests a local Tr1 response.

The development of an autoimmune disease like systemic sclerosis (SSc) is suspected to be driven by an activated T lymphocyte subset, expressing a cytokine profile specific to the disease. To further characterize the type of immune reaction in SSc, we searched for a broad panel of cytokine messenger ribonucleic acids (mRNAs) in T lymphocytes and monocytes/macrophages from paired samples of bronchoalveolar lavage fluid and peripheral blood in 18 patients and 16 age- and sex-matched controls. RNA from CD3(+) T lymphocytes and CD14(+) monocytes/macrophages was examined by means of the reverse transcriptase polymerase chain reaction. SSc alveolar T lymphocytes expressed a cytokine profile suggestive of a mixed Th1/Th2 reaction, showing an increased frequency of mRNA for interleukin (IL)-10, IL-6 and interferon (IFN)γ, while IL-1ß, IFNγ and tumour necrosis factor ß were expressed in blood T lymphocytes in a higher percentage of patients with SSc than controls. SSc alveolar T cells expressed IL-10 mRNA more often than peripheral T cells, a phenomenon not found in controls and which may point at local IL-10 activation/response in SSc lung. Transforming growth factor ß mRNA was present in all alveolar as well as peripheral blood T cell samples in patients and controls. The cytokine mRNA profile in SSc with interstitial lung disease (ILD) was similar to the profile found in SSc without ILD. Our findings point at a mixed Th1/Th2 reaction in SSc and may indicate regulatory T 1 cell activation/response in the lungs of patients with SSc.

Lower airways inflammation in allergic rhinitics: a comparison with asthmatics and normal controls.

BACKGROUND: Allergic rhinitis (AR) and asthma represent a continuum of atopic disease. AR is believed to pre-dispose an individual to asthma. Compared with asthmatics and normal controls, the inflammatory response in the lower airways of rhinitics is not fully elucidated. To test the hypothesis that the inflammatory response in the airways of subjects with AR is at a level intermediate between that in normal controls and asthmatics, we have characterized bronchial inflammation and cytokine mRNA levels in non-asthmatic allergic rhinitics and compared it with subjects with allergic asthma and with normal controls. METHODS: Endobronchial mucosal biopsies were obtained at bronchoscopy from 14 allergic rhinitics, 16 asthmatics and 21 normal controls. Biopsies were embedded into glycol methacrylate resin for immunohistochemical analysis of cellular inflammation and snap frozen for semi-quantitative PCR analysis of cytokine mRNA levels. RESULTS: Airway inflammation in rhinitic subjects was characterized by an increase in submucosal eosinophils, mast cells and the mRNA expression of TNF-alpha, at an intermediate level between healthy and asthmatics. In addition, CD3(+) and CD8(+) lymphocytes in the epithelium, the endothelial expression of vascular adhesion molecule-1 and IL-1 beta mRNA were higher in the allergic rhinitics compared with both normal controls and asthmatics, whereas growth-related oncogene alpha-mRNA was decreased in AR compared with both healthy and asthmatics. Airway inflammation in the asthmatic group was characterized by higher numbers of eosinophils and mast cells, together with an increase in TNF-alpha-mRNA compared with both healthy and rhinitics. IFN-gamma mRNA was the highest in normal controls and lowest in the asthmatics. CONCLUSIONS: In individuals with AR the present data suggest an intermediate state of airway inflammation between that observed in normal individuals and subjects with clinical asthma. It is also indicated that IFN-gamma production by CD8(+) T lymphocytes could be protective against the development of airway hyperresponsiveness. Further work is needed to evaluate this hypothesis.

Airway inflammation in iron ore miners exposed to dust and diesel exhaust.

The aim of the present study was to investigate if underground miners exposed to dust and diesel exhaust in an iron ore mine would show signs of airway inflammation as reflected in induced sputum. In total, 22 miners were studied, once after a holiday of at least 2 weeks and the second time after 3 months of regular work. Control subjects were 21 "white-collar" workers. All subjects completed a questionnaire regarding medical and occupational history, and underwent lung function testing and induced sputum collection. Total and differential cell counts and analyses of the fluid phase of the induced sputum were performed. Sampling of personal exposure to elemental carbon, nitrogen dioxide and inhalable dust was recorded. The average concentrations of inhalable dust, nitrogen dioxide and elemental carbon were 3.2 mg.m-3, 0.28 mg.m-3 and 27 microg.m-3, respectively. Miners had increased numbers of inflammatory cells, mainly alveolar macrophages and neutrophils, and increased concentrations of fibronectin, metalloproteinase-9 and interleukin-10 in induced sputum compared with controls. In conclusion, miners in an underground iron ore mine demonstrated persistent airway inflammation that was as pronounced after a 4-week holiday as after a 3-month period of work underground in the mine.

Altered protein tyrosine phosphorylation in asthmatic bronchial epithelium.

A disease-related, corticosteroid-insensitive increase in the expression of epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase in asthmatic bronchial epithelium has been shown previously by the current authors. To determine whether this is associated with enhanced intracellular signalling, the aim of this study was to evaluate epithelial tyrosine phosphorylation. Bronchial biopsies were analysed for the presence of phosphotyrosine by immunohistochemistry. Bronchial epithelial cells were exposed to EGF, hydrogen peroxide or tumour necrosis factor-alpha in vitro for measurement of tyrosine phosphorylated signalling intermediates and interleukin (IL)-8 release. Phosphotyrosine was increased significantly in the epithelium of severe asthmatics when compared with controls or mild asthmatics; however, in mild asthma, phosphotyrosine levels were significantly decreased when compared with controls. There was no significant difference between phosphotyrosine levels before or after 8 weeks of treatment with budesonide. Stimulation of bronchial epithelial cells resulted in tyrosine phosphorylation of several proteins, including EGFR, Shc and p42/p44 mitogen-activated protein kinase. In the presence of salbutamol, a transient partial suppression of EGFR phosphorylation occurred, whereas dexamethasone was without effect. Neither salbutamol nor dexamethasone inhibited EGF-stimulated IL-8 release. These data indicate that regulation of protein tyrosine kinase activity is abnormal in severe asthma. The epidermal growth factor receptor and/or other tyrosine kinase pathways may contribute to persistent, corticosteroid-unresponsive inflammation in severe asthma.

Increased expression of p38 MAPK in human bronchial epithelium after lipopolysaccharide exposure.

Bacterial endotoxin (lipopolysaccharides (LPS)) is normally present in the wall of Gram-negative bacteria and has potent pro-inflammatory properties. Exposure to LPS has been shown to induce neutrophilic airway inflammation in humans. The aim of this investigation was to study the early inflammatory responses to LPS exposure in human airway mucosa in vivo. In total, 15 healthy nonsmoking volunteers participated. Bronchoscopy was performed on two separate occasions, 3 h after saline inhalation and after inhalation of 50 mug LPS in saline. Endobronchial mucosal biopsy specimens were taken and stained immunohistochemically using a panel of monoclonal antibodies directed against mitogen-activated protein kinases (MAPKs), transcription factors, cytokines, adhesion molecules and inflammatory cells. Expression of p38 MAPK increased as a consequence of LPS exposure, as determined by both total epithelial staining and nuclear location. These two responses were strongly associated. Epithelial expression of interleukin-8 showed a tendency towards a significant increase after LPS compared to saline. Epithelial mast cell numbers were increased after LPS, whereas neutrophil numbers were unchanged. Inhalation of lipopolysaccharide induced activation of the bronchial epithelium, as demonstrated 3 h after exposure by increased expression of p38 mitogen-activated protein kinase and interleukin-8, and may represent early regulatory steps in the subsequent development of a neutrophilic bronchial inflammation.

Repeated daily exposure to 2 ppm nitrogen dioxide upregulates the expression of IL-5, IL-10, IL-13, and ICAM-1 in the bronchial epithelium of healthy human airways.

BACKGROUND: Repeated daily exposure of healthy human subjects to NO2 induces an acute airway inflammatory response characterised by neutrophil influx in the bronchial mucosa AIMS: To assess the expression of NF-kappaB, cytokines, and ICAM-1 in the bronchial epithelium. METHODS: Twelve healthy, young non-smoking volunteers were exposed to 2 ppm of NO2/filtered air (four hours/day) for four successive days on separate occasions. Fibreoptic bronchoscopy was performed one hour after air and final NO2 exposures. Bronchial biopsy specimens were immunostained for NF-kappaB, TNF-alpha, eotaxin, Gro-alpha, GM-CSF, IL-5, -6, -8, -10, -13, and ICAM-1 and their expression was quantified using computerised image analysis. RESULTS: Expression of IL-5, IL-10, IL-13, and ICAM-1 increased following NO2 exposure. CONCLUSION: Upregulation of the Th2 cytokines suggests that repeated exposure to NO2 has the potential to exert a "pro-allergic" effect on the bronchial epithelium. Upregulation of ICAM-1 highlights an underlying mechanism for leucocyte influx, and could also explain the predisposition to respiratory tract viral infections following NO2 exposure since ICAM-1 is a major receptor for rhino and respiratory syncytial viruses.

Ozone-induced bronchial epithelial cytokine expression differs between healthy and asthmatic subjects.

BACKGROUND: Ozone (O3) is a common air pollutant associated with adverse health effects. Asthmatics have been suggested to be a particularly sensitive group. OBJECTIVE: This study evaluated whether bronchial epithelial cytokine expression would differ between healthy and allergic asthmatics after ozone exposure, representing an explanatory model for differences in susceptibility. METHODS: Healthy and mild allergic asthmatic subjects (using only inhaled beta2-agonists prn) were exposed for 2 h in blinded and randomized sequence to 0.2 ppm of O3 and filtered air. Bronchoscopy with bronchial mucosal biopsies was performed 6 h after exposure. Biopsies were embedded in GMA and stained with mAbs for epithelial expression of IL-4, IL-5, IL-6, IL-8, IL-10, TNF-alpha, GRO-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), fractalkine and ENA-78. RESULTS: When comparing the two groups at baseline, the asthmatic subjects showed a significantly higher expression of IL-4 and IL-5. After O3 exposure the epithelial expression of IL-5, GM-CSF, ENA-78 and IL-8 increased significantly in asthmatics, as compared to healthy subjects. CONCLUSION: The present study confirms a difference in epithelial cytokine expression between mild atopic asthmatics and healthy controls, as well as a differential epithelial cytokine response to O3. This O3-induced upregulation of T helper type 2 (Th2)-related cytokines and neutrophil chemoattractants shown in the asthmatic group may contribute to a subsequent worsening of the airway inflammation, and help to explain their differential sensitivity to O3 pollution episodes.

Not 15 but 50% of smokers develop COPD?--Report from the Obstructive Lung Disease in Northern Sweden Studies.

BACKGROUND: The prevalence of chronic obstructive pulmonary disease (COPD) according to guidelines of today seems considerably higher than has been reported also in recent literature. AIM: To estimate the prevalence of COPD as defined by British Thoracic Society (BTS) criteria and the recent global initiative for chronic obstructive lung disease (GOLD) criteria. Further aims were to assess the proportion of underdiagnosis and of symptoms in subjects with COPD, and to study risk factors for COPD. METHODS: In 1996, 5892 of the Obstructive Lung Disease in Northern Sweden (OLIN) Study's first cohort could be traced to a third follow-up survey, and 5189 completed responses (88%) were received corresponding to 79% of the original cohort from December 1985. Of the responders, a random sample of 1500 subjects were invited to a structured interview and a lung function test, and 1237 of the invited completed a lung function test with acceptable quality. RESULTS: In ages >45 years, the prevalence of COPD according to the BTS guidelines was 8%, while it was 14% according to the GOLD criteria. The absolutely dominating risk factors were increasing age and smoking, and approximately a half of elderly smokers fulfilled the criteria for COPD according to both the BTS and the GOLD criteria. Family history of obstructive airway disease was also a risk factor, while gender was not. Of those fulfilling the BTS criteria for COPD, 94% were symptomatics, 69% had chronic productive cough, but only 31% had prior to the study been diagnosed as having either chronic bronchitis, emphysema, or COPD. The corresponding figures for COPD according GOLD were 88, 51, and 18%. CONCLUSIONS: In ages >45 years, the prevalence of COPD according to the BTS guidelines was 8%, and it was 14% according to the GOLD criteria. Fifty percent of elderly smokers had developed COPD. The large majority of subjects having COPD were symptomatic, while the proportion of those diagnosed as having COPD or similar diagnoses was small.

The effects of regular inhaled formoterol and budesonide on preformed Th-2 cytokines in mild asthmatics.

In a recent placebo-controlled study in mild atopic asthmatics, we observed a significant decrease in eosinophils in the bronchial submucosa, after 2 months oftreatment with inhaled formoterol and budesonide. Biopsy material from each treatment group; formoterol (24 microg bid), budesonide (400 microg b. i. d.) and placebo has been further assessed to investigatethe role of Th-2 cytokines by immunohistochemistry using Mabs to eosinophils as an index of inflammation, IL-4 and IL-5. Treatment with formoterol significantly reduced the number of eosinophils (EG2+) in the submucosa and epithelium, but this was not paralleled by changes in cytokine immunoreactivity In contrast, treatment with budesonide significantly reduced both the number of eosinophils (EG2+) and immunoreactivity for IL-4 and IL-5 in the submucosa. Thus, while budesonide has effects on cytokines involved in eosinophil recruitmentthis explanation does not apply tothe eosinopaenia observed with the long-acting beta2 adrenoreceptor agonist formoterol.

Effect of ozone on bronchial mucosal inflammation in asthmatic and healthy subjects.

Epidemiological studies suggestthat asthmatics are more affected by ozone than healthy people. This study tested three hypotheses (1) that short-term exposure to ozone induces inflammatory cell increases and up-regulation of vascular adhesion molecules in airway lavages and bronchial tissue 6 h after ozone exposure in healthy subjects; (2) these responses are exaggerated in subjects with mild allergic asthma; (3) ozone exacerbates pre-existent allergic airways inflammation. We exposed 15 mild asthmatic and 15 healthy subjects to 0.2 ppm of ozone or filtered air for 2 h on two separate occasions. Airway lavages and bronchial biopsies were obtained 6 h post-challenge. We found that ozone induced similar increases in bronchial wash neutrophils in both groups, although the neutrophil increase in the asthmatic group was on top of an elevated baseline. In healthy subjects, ozone exposure increased the expression of the vascular endothelial adhesion molecules P-selectin and ICAM- 1, as well as increasing tissue neutrophil and mast cell numbers. The asthmatics showed allergic airways inflammation at baseline but ozone did not aggravate this at the investigated time point. At 6 h post-ozone-exposure, we found no evidence that mild asthmatics were more responsive than healthy to ozone in terms of exaggerated neutrophil recruitment or exacerbation of pre-existing allergic inflammation. Further work is needed to assess the possibility of a difference in time kinetics between healthy and asthmatic subjects in their response to ozone.

Increased ozone-induced airway neutrophilic inflammation in extracellular-superoxide dismutase null mice.

Extracellular-superoxide dismutase (EC-SOD) exists primarily in the tissue interstitium and the lung contains particularly large amounts of the enzyme. To determine the roles of EC-SOD and extracellularly formed superoxide radicals in the pulmonary response to the common air pollutant ozone, wild-type mice and mice lacking EC-SOD were exposed to 1.5 ppm ozone for 48 h. The exposure resulted in a marked neutrophilic inflammatory reaction observed both in the bronchoalveolar lavage fluid (BALF) and by histopathology of the lungs, which was much stronger in the mice lacking EC-SOD. Unlike the wild-type mice, the null mutants also showed increased levels of interleukin-6 in the BALF. The ozone exposure also resulted in increased airway mucosal permeability and cell damage as indicated by increased protein and lactate dehydrogenase in the BALF. There was, however, no difference between the two groups of mice.The results suggest that extracellular superoxide radicals are important inflammatory mediators in the pulmonary response to ozone, but in the present model, the radical and the infiltrating neutrophils contributed little to the pulmonary injury The data, together with previous findings, support a role for EC-SOD as a modulator of inflammatory reactions.

Effects of budesonide and formoterol on NF-kappaB, adhesion molecules, and cytokines in asthma.

The asthmatic inflammatory response can be attenuated by corticosteroids and in part by beta(2)-agonists. We investigated if these effects are accompanied by a downregulation in nuclear factor kappa B (NF-kappaB), a transcription factor regulating many of the cytokine and adhesion molecule genes expressed in allergic inflammation. Bronchial biopsies were taken before and after 8 wk treatment with formoterol, budesonide, or placebo from atopic asthmatics. Biopsies were processed into glycol methacrylate and stained immunohistochemically for eosinophils (as an index of inflammation), activated and total NF-kappaB, adhesion molecules, and cytokines. After budesonide treatment there was a significant decrease in the number of submucosal cells staining for total NF-kappaB, granulocyte macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha), accompanied by a significant decrease in mucosal eosinophils and expression of vascular cell adhesion molecule-1 (VCAM-1) in the endothelium and interleukin-8 (IL-8) in the epithelium. After formoterol treatment there was a significant decrease in eosinophils and the epithelial expression of activated NF-kappaB, but these changes were not accompanied by reduced immunoreactivity for adhesion molecules or cytokines. We conclude that at least some of the therapeutic efficacy of inhaled corticosteroids is mediated through inhibition of NF-kappaB-regulated gene expression, whereas the reduction in airway eosinophilia by long-acting beta(2)-agonists probably operates through alternative pathways.

Differences in basal airway antioxidant concentrations are not predictive of individual responsiveness to ozone: a comparison of healthy and mild asthmatic subjects.

The air pollutant ozone induces both airway inflammation and restrictions in lung function. These responses have been proposed to arise as a consequence of the oxidizing nature of ozone, depleting endogenous antioxidant defenses with ensuing tissue injury. In this study we examined the impact of an environmentally relevant ozone challenge on the antioxidant defenses present at the surface of the lung in two groups known to have profound differences in their antioxidant defense network: healthy control (HC) and mild asthmatic (MA) subjects. We hypothesized that baseline differences in antioxidant concentrations within the respiratory tract lining fluid (RTLF), as well as induced responses, would predict the magnitude of individual responsiveness. We observed a significant loss of ascorbate (ASC) from proximal (-45.1%, p <.01) and distal RTLFs (-11.7%, p <.05) in healthy subjects 6 h after the end of the ozone challenge. This was associated (Rs, -0.71, p <.01) with increased glutathione disulphide (GSSG) in these compartments (p =.01 and p <.05). Corresponding responses were not seen in asthmatics, where basal ASC concentrations were significantly lower (p <.01) and associated with elevated concentrations of GSSG (p <.05). In neither group was any evidence of lipid oxidation seen following ozone. Despite differences in antioxidant levels and response, the magnitude of ozone-induced neutrophilia (+20.6%, p <.01 [HC] vs. +15.2%, p =.01 [MA]) and decrements in FEV(1) (-8.0%, p <.01 [HC] vs. -3.2%, p <.05 [MA]) did not differ between the two groups. These data demonstrate significant differences between the interaction of ozone with RTLF antioxidants in MA and HC subjects. These responses and variations in basal antioxidant defense were not, however, useful predictive markers of group or individual responsiveness to ozone.

Sodium cromoglycate attenuates pulmonary inflammation without influencing bronchial responsiveness in healthy subjects exposed to organic dust.

BACKGROUND: Inhalation of organic dust from a pig house induces airway inflammation and increases bronchial responsiveness to methacholine in healthy subjects. OBJECTIVE: To study whether sodium cromoglycate influences the airway inflammatory reaction and the increase in airway responsiveness induced by inhalation of organic dust. METHODS: Bronchoalveolar and nasal lavages, and bronchial methacholine challanges were performed and blood samples were drawn in 32 healthy subjects before and after exposure to dust in a pig farm. Sodium cromoglycate was inhaled (20 mg, twice a day) and administered intranasally (5.2 mg, twice a day) by 16 and a corresponding placebo was given to the other 16 healthy controls for two weeks prior to exposure. RESULTS: Exposure induced a significant increase in inflammatory cells and soluble components (pro-inflammatory cytokines, inflammatory mediators) in bronchoalveolar and nasal lavage fluid in both groups. The increase in neutrophils, interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha as well as myeloperoxidase and soluble intracellular adhesion molecule (ICAM)-1 in bronchoalveolar lavage (BAL) fluid was significantly reduced by treatment with sodium cromoglycate. Although sodium cromoglycate inhalation largely influenced a variety of inflammatory indices in bronchoalveolar lavage fluid it had no effect on the increase in bronchial responsiveness to methacholine. CONCLUSION: Sodium cromoglycate alters the airway inflammatory response to inhaled organic dust without influencing the dust-induced increase in bronchial responsiveness to methacholine.

Incidence of physician-diagnosed asthma in adults--a real incidence or a result of increased awareness? Report from The Obstructive Lung Disease in Northern Sweden Studies.

Only limited data are available about the incidence of asthma based on longitudinal prospective studies. Further, the results from different studies on incidence vary considerably depending on the age composition of the cohorts under study, the used methods and the criteria for disease. Also among adults high incidence rates have been reported during recent years. The aim of this study was to examine to what extent the incidence of physician-diagnosed asthma could be explained by a real incidence of the disease, and to what extend by an increased diagnostic activity or altered diagnostic praxis. Another aim was to study risk factors for asthma based on incident cases. Three cross-sectional surveys have been performed in the same population sample living in the northern-most province of Sweden, Norrbotten. The first survey was performed in 1986, and 5698 subjects, 86% of those invited, responded to a postal questionnaire. Of these, 4754 subjects (83%) participated at the third survey in 1996. After exclusion of all subjects who had reported that they had asthma in 1986, or had been classified as having asthma in 1986, 68 men and 98 women (P=0.02) reported in 1996 that they had been diagnosed as having asthma by a physician. Thus, the cumulative incidence for the 10-year period was 3.2% among men and 4.5% among women. After correction for subjects who already in 1986 had reported symptoms common in asthma, or had been classified as having chronic bronchitis, 97 subjects with incident asthma remained, which corresponded to an annual incidence rate among men of 1.7 and among women of 2.9/1000 persons year(-1) (P=0.1). Clinical examinations confirmed asthma in a large majority of these 97 subjects. Significant risk factors were family history of asthma, both ex- and current smoking, and female sex. The socio-economic groups manual workers and assistant non-manual employees were associated with incident asthma, although not significantly. The increasing prevalence of asthma among adults during recent 10-20 years may to a considerable extent be explained by an increased diagnostic activity or altered diagnostic praxis. Use of different methods when measuring incidence may in part explain the extremely diverging incidence rates of asthma found in different studies.

Diesel exhaust enhances airway responsiveness in asthmatic subjects.

Particulate matter (PM) pollution has been associated with negative health effects, including exacerbations of asthma following exposure to PM peaks. The aim of the present study was to investigate the effects of short-term exposure to diesel exhaust (DE) in asthmatics, by specifically addressing the effects on airway hyperresponsiveness, lung function and airway inflammation. Fourteen nonsmoking, atopic asthmatics with stable disease, on continuous treatment with inhaled corticosteroids, were included. All were hyperresponsive to methacholine. Each subject was exposed to DE (particles with a 50% cut-off aerodynamic diameter of 10 microm (PM10) 300 microg x m(-3)) and air during 1 h on two separate occasions. Lung function was measured before and immediately after the exposures. Sputum induction was performed 6 h, and methacholine inhalation test 24 h, after each exposure. Exposure to DE was associated with a significant increase in the degree of hyperresponsiveness, as compared to after air, of 0.97 doubling concentrations at 24 h after exposure (p < 0.001). DE also induced a significant increase in airway resistance (p=0.004) and in sputum levels of interleukin (IL)-6 (p=0.048). No changes were detected in sputum levels of methyl-histamine, eosinophil cationic protein, myeloperoxidase and IL-8. This study indicated that short-term exposure to diesel exhaust, equal to high ambient levels of particulate matter, is associated with adverse effects in asthmatic airways, even in the presence of inhaled corticosteroid therapy. The increase in airway responsiveness may provide an important link to epidemiological findings of exacerbations of asthma following exposure to particulate matter.

Nitric oxide (NO) in exhaled air after experimental ozone exposure in humans.

We hypothesized that ozone, a common air pollutant, potent in producing airway inflammation, would increase the production of exhaled nitric oxide (NO). If so, measurement of exhaled NO could potentially be a valuable tool in population studies of air pollution effects. Eleven healthy non-smoking volunteers were exposed to 0.2 ppm ozone (O3) and filtered air for 2h on two separate occasions. Exhaled NO and nasal NO were measured before and on five occasions following the exposures. Changes in exhaled and nasal NO after ozone exposure were adjusted for changes after air exposure. There was a slight decrease in exhaled NO (-0.6; -3.1-1.2 ppb) (median and 95% confidence interval) and of nasal NO (-57; -173-75 ppb) directly after the ozone exposure. No significant changes in exhaled or nasal NO were however found 6 or 24 h after the exposure. Within the examined group, an O3 exposure level proven to induce an airway inflammation caused no significant changes in exhaled or nasal NO levels. Hence, the current study did not yield support for exhaled NO as a useful marker of ozone-induced oxidative stress and airway inflammation after a single exposure. This contrasts with data for workers exposed to repeated high peaks of ozone. The potential for exhaled NO as a marker of oxidative stress therefore deserves to be further elucidated.

The anti-inflammatory profile of inhaled corticosteroids combined with salmeterol in asthmatic patients.

Inhaled corticosteroid (ICS) therapy such as fluticasone propionate (FP) is effective in moderate-to-severe asthma, but for patients on ICS who still experience symptoms, treatment guidelines recommend either increasing the dose of ICS or adding a long-acting beta2-agonist such as salmeterol or formoterol. Several studies have now shown that adding salmeterol provides greater clinical benefit than increasing the dose of ICS, raising the question of whether salmeterol has an additive or complementary anti-inflammatory effect to that of ICS. Recent studies on bronchial biopsies and bronchoalveolar lavage from asthmatic patients treated with either salmeterol. FP or placebo in addition to low-dose ICS have demonstrated that addition of salmeterol produces independent or additional reductions in several pro-inflammatory cells, cytokines and cell adhesion molecules compared with FP. Such complementary anti-inflammatory effects may explain the improved control of asthma symptoms and exacerbations observed when salmeterol is added to low-dose ICS therapy, and may help to modify the long-term sequelae of asthma. These findings also indicate, contrary to earlier speculation, that salmeterol does not have a pro-inflammatory effect or mask persistent airway inflammation. This review presents the results of recent studies and suggests possible mechanisms for the additional antiinflammatory effects of salmeterol.