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Notes: Devalia JL, Bayram H, Rusznak C, Calderón M, Sapsford RJ, Abdelaziz MA, Wang J, Davies RJ. Mechanisms of pollution-induced airway disease: in vitro studies in the upper and lower airways.Evidence from both epidemiological and laboratory-based studies suggests that increased exposure to liquid petroleum and gas-derived air pollutants [nitrogen dioxide (NO2), ozone, and respirable particulate matter] may play a role in the clinical manifestation of both allergic and non-allergic airway disease. The mechanisms and cell types involved in pollutant-mediated effects in the airways, however, are not clear. In vitro studies have suggested that human fibroblasts, B-lymphocytes, alveolar macrophages, and epithelial cells/cell lines may be involved. Studies of fibroblasts and macrophages have demonstrated that exposure to ozone results in decreased cell viability and increased release of pro-inflammatory mediators from macrophages. Similarly, studies of B-lymphocytes have demonstrated that exposure to diesel exhaust particles (DEP) enhances the synthesis of immunoglobulin E by these cells. The airway epithelial cells have received the greatest attention in mechanistic studies of air pollution-induced airway disease and suggest that these cells are likely to play a pivotal role in the pathogenesis of airways disease. Various studies have demonstrated that exposure of nasal or bronchial epithelial cells to NO2, ozone, and DEP results in significant synthesis and release of pro-inflammatory mediators, including eicosanoids, cytokines, and adhesion molecules. Additionally, evidence suggests that epithelial cells of atopic individuals release significantly greater amounts of cytokines such as granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-6 (IL-6), IL-8, and regulated on activation, normal T-cell expressed and secreted (RANTES), on exposure to NO2 and ozone. Studies investigating the biological relevance of epithelial cell-derived pro-inflammatory mediators have shown that these enhance eosinophil chemotaxis and eosinophil adherence to endothelial cells, suggesting that pollution-induced inflammation of the airways is likely to be influenced by modulation of epithelial synthesis and release of these mediators.

Notes: Davies RJ, Rusznak C, Calderón MA, Wang JH, Abdelaziz MM, Devalia JL. Allergen-irritant interaction and the role of corticosteroids.Studies of exposure to air pollutants, such as ozone and nitrogen dioxide (NO2)± sulphur dioxide (SO2), have demonstrated that these agents, either individually or in combination, increase the airway response of both asthmatics and allergic rhinitics to inhaled allergen. Other studies have demonstrated that exposure to these pollutants significantly increased the levels of eosinophil cationic protein (ECP) in the nasal secretions of both asthmatics and allergic rhinitics, suggesting that pollutants may prime eosinophils for subsequent activation by allergen. More recently, our studies have demonstrated that treatment with inhaled corticosteroids, such as fluticasone propionate, significantly attenuated pollution+ allergen-induced release of ECP in allergic rhinitics. Although the mechanisms underlying the potentiating effects of pollutants on allergen-induced changes in the airways of allergic individuals are not fully understood, in vitro studies have suggested that airway epithelial cells may play an important role, since they can synthesize a variety of cytokines and adhesion molecules which influence the activity of eosinophls and other inflammatory cells. Studies of nasal epithelial cells cultured from biopsies of atopic rhinitic and atopic non-rhinitic individuals have shown that they constitutively release significantly greater quantities of pro-inflammatory cytokines than nasal epithelial cells of non-atopic individuals, and that the release of these cytokines is greater from cells of atopic rhinitics during the pollen season. Furthermore, exposure of the cells of rhinitics to ozone led to an even greater release of these cytokines, and this effect was attenuated by treatment with fluticasone propionate and beclomethasone dipropionate.Taken together, the results described above provide evidence to suggest that atmospheric pollutants, such as ozone or the combination of NO2 and SO2, increase the bronchial response of mild asthmatic subjects to inhaled allergen, and that this may persist for a period of 24–48 h after exposure. Acute exposure to ozone or NO2 ‘primes’ the eosinophils for subsequent activation by allergen, and pretreatment with FP attenuates both the pollution-induced eosinophil priming and allergen-induced increase in the number of EGZstaining cells in the bronchial mucosa, suggesting that FP treatment may modulate airway inflammation by influencing the activity of eosinophils, and perhaps other inflammatory cell types.At the cellular level, airway epithelial cells probably play an important role in the initiation and maintenance of airway inflammation, since these cells express and release pro-inflammatory mediators which influence the recruitment and activation of inflammatory cells, such as neutrophils and eosinophils, in the airways. Nasal epithelial cells from both atopic non-rhinitics and atopic rhinitics release sigmficantly greater amounts of IL-8, GM-CSF and TNFα, than cells from non-atopic non-rhinitics. The cells of atopic rhinitics release significantly greater quantities of these cytokines during the pollen season, compared with outside of the pollen season, and exposure of these cells to ozone further enhances the release of these cytokines, an effect which can be attenuated by incubating the cells with FP or BDI?

Notes: Several studies have shown that exposure to cigarette smoke and/or house dust mite (HDM) can lead to increased airway inflammation in susceptible individuals. The underlying mechanisms, however, are not defined.To investigate the interaction between cigarette smoke and HDM allergen on mediator release from primary cultures of human bronchial epithelial cells.Confluent human bronchial epithelial cell cultures were exposed to cigarette smoke in the absence or presence of HDM allergen and investigated for the release of IL-8, IL-1β, and sICAM-1. Damage to the epithelial cells themselves was assessed by release of 51Cr. On separate occasions, we investigated the effect of PTL11028, a highly potent and selective Der p1 inhibitor, on HDM allergen-induced release of IL-8, following activation of HDM allergen by incubation with cysteine. The effect of cigarette smoke exposure on the stability of these released mediators in prepared solutions in the absence/presence of reduced glutathione was also studied.Both HDM allergens and short-term (20 min) cigarette smoke exposure led to a significantly increased release of IL-8, IL-1β and sICAM-1 from the epithelial cell cultures. Longer exposure (1–6 h) to cigarette smoke led to a dramatic decrease in the amount of these mediators detected in the culture medium. Whilst incubation of epithelial cultures with HDM allergen did not cause any significant change in the release of 51Cr from pre-loaded cells, cigarette smoke on its own led to a marked, exposure and incubation-time dependent increase in the release of 51Cr. Incubation with HDM allergen led to a significant, dose and time-dependent increase in the release of IL-8, which was further enhanced when the allergen extract was pre-activated with cysteine. This effect was completely abrogated by PTL11028, a novel Der p1 inhibitor. Prepared solutions of various concentrations of IL-8, IL-1β and sICAM-1 exposed to cigarette smoke demonstrated a dramatic exposure time-dependent decrease in the detectable amount of these mediators, an effect which was abrogated by GSH.HDM-induced airway inflammation may include Der p-mediated release of inflammatory mediators from epithelial cells. Additionally, short-term cigarette smoke exposure may induce airway inflammation by release of inflammatory mediators from these cells, an effect which may be potentiated by Der p allergens. Longer term cigarette smoke exposure may cause damage to epithelial cells and changes in the structure of inflammatory mediators.

Notes: Background Although epidemiological as well as in vivo exposure studies suggest that ozone (O3) and nitrogen dioxide (NO2) may play a role in airway diseases such as asthma, the underlying mechanisms are not clear.Objective Our aim was to investigate the effect of O3 and NO2 on the permeability of human bronchial epithelial cell (HBEC) cultures obtained from non-atopic non-asthmatic (non-asthmatics) and atopic mild asthmatic (asthmatics) individuals.Methods We cultured HBECs from bronchial biopsies of non-asthmatics and asthmatics, and exposed these for 6 h to air, 10 to 100 parts per billion (p.p.b.) O3, or to 100 to 400 p.p.b. NO2, and assessed changes in electrical resistance (ER) and movement of 14C-BSA across the cell cultures.Results Although exposure to either O3 or NO2 did not alter the permeability of HBEC cultures of non-asthmatics, 10 to 100 p.p.b. O3 and 400 p.p.b. NO2 significantly decreased the ER of HBEC cultures of asthmatics, when compared with exposure to air. Additionally, 10, 50 and 100 p.p.b. O3 led to a significant increase in the movement of 14C-BSA across asthmatic HBEC cultures, after 6 h of exposure (medians = 1.73%; P 〈 0.01, 1.50%; P 〈 0.05 and 1.53%, P 〈 0.05, respectively), compared with air exposed cultures (median = 0.89%). Similarly, exposure for 6 h to both 200 and 400 p.p.b. NO2 significantly increased the movement of 14C-BSA across asthmatic HBEC cultures, when compared with air exposure. A comparison of data obtained from the two study groups demonstrated that 10 to 100 p.p.b. O3- and 200 to 400 p.p.b. NO2-induced epithelial permeability was greater in cultures of asthmatics compared with non-asthmatics.Conclusion These results suggest that HBECs of asthmatics may be more susceptible to the deleterious effects of these pollutants. Whether in patients with asthma the greater susceptibility of bronchial epithelial cells to O3 and NO2 contributes to the development of the disease, or is a secondary characteristic of this condition, remains to be determined.

Notes: Evidence suggests that allergic disease is becoming more common, particularly in industrialized societies. Two studies of schoolchildren from Aberdeen, Scotland aged 8–13 years were undertaken in 1964 and 1989 using identical questionnaires, and found that the reported prevalence of asthma had risen from 4.1% to 10.2% during this period, hay fever from 3.2% to 11.9% and eczema from 5.3% to 12%. Indication that air pollution may contribute to this increase has come from several studies. In Japan, allergic rhinoconjunctivitis was found to be more prevalent in individuals living near motorways than in cedar forests. Severe asthma also occurs more commonly than mild asthma in children living in polluted areas. Exercise-induced asthma and the use of asthma medication were twice as high in a town near two power stations compared with a non-polluted town. A recent study in Finland showed that admissions to hospital with severe asthma correlated with atmospheric levels of nitrogen dioxide. Deterioration in peak flow recordings in asthmatics and exacerbations of symptoms in hay fever sufferers correlate with ambient levels of ozone. Elucidation of the mechanisms by which exposure to air pollutants may influence the frequency of allergic disease or exacerbate symptoms has come from in vitro and in vivo experiments in animals and man. Animals exposed to ozone, sulphur dioxide, nitrogen dioxide and particles from diesel exhaust, together with allergens, show more ready development of allergic sensitization compared with those exposed to allergen alone. The dose of allergen necessary to produce a 20% fall in FEV1 (forced expiratory volume in 1 second) in mild asthmatics is reduced by previous exposure to ozone or a mixture of nitrogen dioxide and sulphur dioxide. It has also been suggested that the allergic potency of pollen grains may be increased when they are coated in pollutants. Bronchial and nasal lavage studies have shown that air pollutants can induce an influx of inflammatory cells and proinflammatory cytokines into the respiratory tract. Studies on human epithelial cells cultured to confluence in vitro have indicated that exposure to nitrogen dioxide can decrease ciliary beat frequency which would, in theory, reduce allergen clearance and increase the risk of sensitization. Further, exposure of these cells to either ozone or nitrogen dioxide induces the release of inflammatory mediators, such as leukotriene C4, and proinflammatory cytokines, including granulocyte-macrophage colony-stimulating factor, tumour necrosis factor-α and interleukin-8. This effect can be attenuated by the use of anti-inflammatory drugs.