R. J. Davies

Mechanisms of pollution-induced airway disease: in vitro itudies in the upper and lower airways

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.

Differences between cytokine release from bronchial epithelial cells of asthmatic patients and non-asthmatic subjects : Effect of exposure to diesel exhaust particles

Background: Recent evidence suggests that the airways of asthmatics are more susceptible to adverse effects of air pollutants than the airways of non–asthmatics, but the underlying mechanisms are not clear. Methods: We have cultured bronchial epithelial cells (HBEC) from biopsies of atopic mild asthmatic patients and non–atopic non–asthmatic subjects, and investigated constitutive and diesel exhaust particles (DEP)–induced release of several pro–inflammatory mediators. Results: HBEC of asthmatic patients constitutively released significantly greater amounts of IL–8, GM–CSF and sICAM–1 than HBEC of non–asthmatic subjects. RANTES was only released by HBEC of asthmatic patients. Incubation of the asthmatic cultures with 10 μg/ml DEP significantly increased the release of IL–8, GM–CSF and sICAM–1 after 24 h. In contrast, only the higher concentrations of 50–100 μg/ml DEP significantly increased the release of IL–8 and GM–CSF from HBEC of non–asthmatics. Conclusions: These results suggest that the increased sensitivity of the airways of asthmatics to air pollutants such as DEP may, at least in part, be a consequence of greater constitutive and pollutant–induced release of specific pro–inflammatory mediators from their bronchial epithelial cells.

Airway epithelial cells

The epithelial lining of the airways forms the first line of defence against toxic and infectious agents in the inspired air. Although airway epithelial cells have traditionally been seen to play a vital role in providing an impermeable barrier and clearing the airways of noxious inhaled agents, through efficient mucociliary clearance, there is now increasing evidence to suggest that airway epithelial cells play a more important physico-chemical role. Several studies have demonstrated that epithelial cells are capable of synthesising and releasing several biologically active mediators which directly or indirectly influence the activity of inflammatory cells important in allergic airway diseases, including allergic rhinitis and asthma [1].

Efficacy and Tolerability Comparison of Ebastine 10 and 20mg with Loratadine 10mg

EnAbstract Objective: To compare the dose-related efficacy and tolerability of the oral H1 antihistamine ebastine (10 or 20mg) with a reference drug, loratadine (10mg), in the once-daily treatment of perennial allergic rhinitis (PAR). Patients and Methods: The trial was conducted in 317 patients (aged 12 to 68 years) with ongoing symptoms of PAR. Mean 24-hour diary card symptom severity scores (0–3) were compared as changes from baseline between the randomised, double-blind treatment groups over a 4-week period. Results: Symptom scores, including both ‘perennial index’ (PIN = sneezing + nasal itching + discharge) and total ‘nasal index’ (TNI = PIN + nasal stuffiness) showed statistically significantly greater improvements with ebastine 10 or 20mg than with loratadine 10mg for all parameters except sneezing, itching and ocular symptoms. The mean TNI scores were reduced by 44, 47 and 32%, respectively, over 4 weeks, and treatment differences were apparent from week 1 onwards. Patient and physician final opinions (percentage of patients improved) were also significantly in favour of ebastine (79 to 85%) vs loratadine (65 to 66%). The treatments were equally well tolerated and no serious adverse events occurred. Conclusion: This study found ebastine 10 or 20mg to be more effective than loratadine 10mg for the treatment of PAR.

Allergen‐irritant interaction and the role of corticosteroids

Davies RJ, Rusznak C, Calderón MA, Wang JH, Abdelaziz MM, Devalia JL. Allergen‐irritant interaction and the role of corticosteroids.

Pollution-induced airway disease and the putative underlying mechanisms

ConclusionsTaken together, the findings of both epidemiological and laboratory-based studies provide evidence that exposure to air pollutants generated from petrol and diesel-burning engines are likely to precipitate attacks of asthma and rhinitis, and possibly contribute to the increase in prevalence of these disorders. The mechanisms by which pollutants exert their effects may be either indirect (modulation of allergenicity of airborne allergens) or direct:1.Increased epithelial damage and permeability;2.Decreased ciliary activity;3.Depletion of naturally occurring antioxidants; and4.Release of proinflammatory cytokines and cell adhesion molecules, which orchestrate the functions of inflammatory cells, such as eosinophils, mast cells, and lymphocytes (Fig. 4).

Anti-allergic properties of antihistamines in humans

Summary The recent finding that an antihistamine administered regularly to 1–2 years old children with atopic dermatitis, prevented the subsequent development of asthma in those allergic to grass pollen or house dust mite has focused attention on the properties of this class of therapeutic agents. Is this effect simply due to antagonism of histamine, which may have wider actions in the development of airway inflammation than previously suspected, or is it a result of the anti-allergic properties exhibited by the second generation antihistamines? There are now many in vivo studies which have demonstrated that antihistamines decrease mast/basophil cell mediator release, inflammatory cell infiltration in allergic disease, and expression of adhesion molecules on epithelial cells. Numerous in vitro studies support these findings, extending the anti-inflammatory properties of antihistamines to decreasing eosinophil migration and release of pro-inflammatory mediators. We have established primary cultures of epithelial cells from nasal biopsies from seasonal allergic rhinitics outside the pollen season, and studied the effect of 0 to 10−3M fexofenadine, the main active metabolite of terfenadine, on activated eosinophil-induced changes in electrical resistance (a measure of permeability of epithelial cultures) and release of pro-inflammatory cytokines and adhesion molecules. 10−9 to 10−3M fexofenadine significantly inhibited eosinophil-induced increases in the permeability of the epithelial cell cultures and the release of IL-8, GM-CSF and sICAM-1. In addition, 10−6 to 10−3M fexofenadine significantly inhibited cytokine-induced eosinophil chemotaxis and adhesion of these cells to endothelial cells.

Mechanisms of pollution-induced allergy and asthma

Summary Evidence from a number of epidemiological and exposure chamber studies suggests that an increase in air pollutants, such as ozone (O3), oxides of nitrogen (NOx), respirable particulates (PM10) and volatile organic chemicals (VOCs), resulting from increased use of liquid petroleum gas or kerosene, may be linked to an increase in the prevalence of allergic disease, particularly in the developed countries. Several studies have indicated that there is an association between hospital emergency room visits due to asthma and increased air pollution. Studies from Japan and Germany have demonstrated that there is a significant association between increased vehicle exhaust pollution and increased incidence of rhino-conjunctivitis and hay-fever. Exposure chamber studies have shown that acute inhalation of air pollutants such as O3, nitrogen dioxide (NO2) and sulphur dioxide (SO2), either individually or in combination, may increase the airway response to inhaled allergen in atopic asthma. Studies investigating the mechanisms underlying pollution-induced pathogenesis of allergic airways disease have demonstrated that there is an association between air pollutants and an increase in mean total/specific serum IgE level and increased positive skin reactions. Bronchial and nasal lavage studies have shown that O3 and NO2 can induce significant increase in epithelial damage and permeability, an influx of inflammatory cells and release of pro-inflammatory cytokines into the respiratory tract. We have shown that exposure of human bronchial epithelial cells to NO2, O3, diesel exhaust particles (DEP) and cigarette smoke (CS), in vitro, leads to significant epithelial cell dysfunction and significant release of proinflammatory cytokines such as interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α), granulocytemacrophage colony stimulating factor (GM-CSF) and regulated on activation, normal T-cell expressed and secreted (RANTES). We have also shown that epithelial cells of atopic individuals release significantly greater amounts of these cytokines. The epidemiological and direct in vivo and in vitro exposure studies presented in this paper provide evidence that exposure to pollutants precipitate attacks of asthma and may also be one of several causes of the increase in the prevalence of this disorder. The mechanisms by which pollutants exert their effect are likely to be direct and dose-dependent actions on epithelial cells leading to changes in permeability and generation of pro-inflammatory mediators including cytokines.