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Biomedical subjects

P H Howarth

Publications and source records attributed to P H Howarth.

At least 55 records · Page 3Linked to original sources
PubMed1998

Exhaled nitric oxide; relationship to clinicophysiological markers of asthma severity.

Bronchial asthma is an airway disorder associated with bronchial hyperresponsiveness, variable airflow obstruction and elevated levels of nitric oxide (NO) in exhaled air. The variables all reflect, in part, the underlying airway inflammation in this disease. To understand their interrelationships we have investigated the relationship between exhaled NO levels and clinicophysiological markers of asthma severity. Twenty-six steroid naive atopic asthmatics participated in the analysis. All were given diary cards and were asked to record their peak expiratory flow (PEF) rates twice daily together with their asthma symptom scores and beta-agonist use. Diary cards were collected 2 weeks later and measurements of exhaled NO levels, FEV1 and histamine bronchial hyperreactivity (PC20 histamine) were undertaken. Exhaled NO levels were significantly higher in our study population than in normal control subjects and correlated negatively with PC20 histamine (r = -0.51; P = 0.008) and positively with PEF diurnal variability (r = 0.58; P = 0.002), but not with symptom scores, beta-agonist use of FEV1 (%). We conclude that a significant relationship exists between exhaled NO levels and the two characteristic features and markers of asthma severity, namely bronchial hyperreactivity and PEF diurnal variability. The lack of correlation between symptom score and beta-agonist use, of FEV1 (%) predicted and exhaled NO suggests that these measures are reflective of differing aspects of asthma.

Adolescent↗
PubMed1998

Inflammatory mediators in naturally occurring rhinitis.

BACKGROUND: The mediators released during the allergic inflammatory reaction induce the clinical symptoms of the allergic disease and although there have been numerous studies investigating mediator release in allergen challenge models of allergic rhinitis very few have extended this approach to the study of natural disease. OBJECTIVE: The aim of this investigation was therefore to measure mast cell and eosinophil mediator levels and indices of vascular permeability in naturally occurring rhinitis. METHODS: Three groups of subjects were studied, normal non-rhinitics, seasonal allergic rhinitics in and out of the grass pollen season and perennial allergic rhinitics. Mediators were recovered using the technique of nasal lavage and the levels of tryptase, histamine, eosinophil cationic protein and albumin were determined. In addition, eosinophils were enumerated in nasal smears as an indices of underlying inflammation. RESULTS: The levels of tryptase, eosinophil cationic protein and albumin were significantly higher in the lavage recovered from the symptomatic seasonal allergic rhinitics than when asymptomatic (P = 0.05, P = 0.003, P = 0.009, respectively). These levels of eosinophil cationic protein and albumin were also significantly higher than those of the normal non-rhinitics (P = 0.0008, P = 0.0.003, respectively). In the perennial allergic rhinitics the levels of tryptase, eosinophil cationic protein and albumin were higher than the normal non-rhinitics (P < 0.0001, P = 0.0003, P = 0.0001, respectively). The levels of tryptase and histamine were higher in the perennial allergic rhinitics than the seasonal allergic rhinitics (P = 0.0003, P = 0.006, respectively). These changes in mediator levels were accompanied by a significant influx of eosinophils into the nasal mucosa of both the symptomatic seasonal rhinitics, compared with asymptomatic (P = 0.04) and normal controls (P = 0.0006) and the perennial rhinitics compared to normal controls (P = 0.03). CONCLUSION: These results indicate that in both naturally occurring seasonal allergic rhinitis and perennial allergic rhinitis mast cell and eosinophil activation occurs and this is accompanied by an increase in vascular permeability. These measurements in lavage fluid provide a method of monitoring the mucosal cellular events in response to therapy.

Adult↗
PubMed1998

Is allergy increasing?--early life influences.

Data from epidemiological studies conducted in several countries worldwide have revealed that the prevalences of allergic conditions, including allergic rhinitis, asthma and eczema, have increased from the 1940s/50s to the 1990s. These allergic conditions involve specific IgE-mediated responses, and a few studies have demonstrated that IgE levels have increased in some communities over time in a manner similar to the incidences of allergic conditions. The predisposition for atopy appears to be determined in early life, and evidence indicates that events occurring in utero and in infancy can influence the future development of atopy. The intrauterine environment favours TH2 cell development and IgE production and could predispose to atopy. It can be hypothesized that dietary or other factors favouring TH2 proliferation might contribute to the development of atopic disease. Conversely, early infection has been found to have a negative association with the development of atopy, perhaps through promotion of a TH response; the reduction in infection in the very young as a consequence of modern healthcare may have contributed to the increase in atopic disease. Thus, it is a plausible hypothesis that changes in the conditions of the intrauterine environment and/or in infancy (for example, in nutrition and in rates of infection) may explain the observed increases in atopy and allergic conditions.

Age Distribution↗
PubMed1998

Cyclosporin A treatment and airways inflammation in corticosteroid-dependent asthma.

Cyclosporin A is a potent immunosuppressive agent which inhibits activation of T cells and other inflammatory cells. It has been shown to be of clinical benefit in patients with corticosteroid-dependent asthma, but there are no data on its in vivo effects on airways inflammation. In this report, we describe the case of a 47-year-old man with chronic severe corticosteroid-dependent asthma who made a dramatic clinical response to therapy with cyclosporin A. Fibreoptic bronchoscopy with bronchoalveolar lavage and endobronchial biopsy were performed before and after a 12-month period of treatment with cyclosporin A and demonstrated a concomitant reduction in airway inflammatory indices.

Adrenal Cortex Hormones↗
PubMed1997

Immunoreactive endothelin in bronchial biopsy specimens: increased expression in asthma and modulation by corticosteroid therapy.

BACKGROUND: The human endothelin (ET) family comprises three 21-amino-acid peptides, which are potent bronchoconstrictors and have a number of other biologic properties relevant to the pathophysiology of asthma. OBJECTIVE: We sought to compare the expression of immunoreactive ET in bronchial biopsy specimens from subjects with asthma treated only with inhaled beta2-agonists, subjects with asthma treated with beta2-agonists and corticosteroids, and control subjects without asthma. METHODS: Biopsy specimens were obtained by fiberoptic bronchoscopy and stained immunohistochemically with a specific ET antiserum. Epithelial ET expression was quantitated by using a computer-assisted system of image analysis. Numbers of inflammatory cells and depth of subepithelial collagen deposition were also determined. RESULTS: Immunoreactive ET was principally localized in the airway epithelium. The proportion of epithelium immunostained was significantly increased in the subjects with asthma not treated with steroids (35.4% +/- 3.8%) compared with that of both the control subjects (16.2% +/- 1.9%, p < 0.0001) and the subjects with asthma treated with steroids (14.3% +/- 2.0%, p < 0.0001). The last two groups did not differ significantly from one another. There were no significant correlations between ET expression and either physiologic parameters or indexes of airway inflammation and remodeling. CONCLUSION: Bronchial epithelial expression of immunoreactive ET is increased in subjects with asthma receiving treatment only with beta2-agonists but not in subjects with asthma also receiving corticosteroid therapy. These findings are consistent with the hypothesis that ET is implicated in the pathophysiology of asthma.

Adrenal Cortex Hormones↗
PubMed1997

What is the nature of asthma and where are the therapeutic targets?

The characterisation of chronic asthma as an inflammatory condition of the human airway, associated with heightened airway responsiveness to a variety of bronchial stimuli, has lead to the clarification of therapeutic strategies. These strategies have focused on bronchodilation and attenuation of airway inflammation. Inhaled corticosteroids effectively reduce chronic inflammation and produce substantial symptomatic relief in most patients. This article examines the pathophysiology of asthma and discusses the interpretation of current methods of assessment, and the targets and actions of inhaled anti-asthmatic drugs in relationship to central and peripheral airway events.

Airway Obstruction↗
PubMed1997

House-dust mite allergen Der p 1: amount or concentration?

There is a lack of consensus as to the best way to quantify settled house-dust mite Der p 1 allergen from planar and nonplanar surfaces. To investigate the most appropriate measure of settled house-dust mite Der p 1 allergen, we determined the relationship between Der p 1 allergen content and collected dust weight from planar-surface (mattress) and nonplanar-surface (living-room) samples in 58 homes. There was a direct relationship between Der p 1 content and dust weight for both planar-surface (mattress, n = 217) samples (r = 0.50, P < 0.0001) and nonplanar-surface (living-room, n = 48) samples (r = 0.61, P < 0.0001). Correction for the surface area of the planar surface (mattress) vacuum-cleaned resulted in no additional benefit. We conclude that expression of Der p 1 levels per weight of collected dust appears to be the best method for both planar and nonplanar surfaces.

Allergens↗
PubMed1997

Transforming growth factor-beta 1 in asthma. Measurement in bronchoalveolar lavage fluid.

Airway wall remodeling is an established pathological feature in asthma. Its causes are not well understood, but one mediator of potential relevance is transforming growth factor-beta 1 (TGF-beta 1). We have measured levels of immunoreactive TGF-beta 1 in bronchoalveolar lavage (BAL) fluid from clinically stable atopic asthmatics and healthy control subjects. We have also examined the influence of allergen exposure on TGF-beta 1 release in the airways using a segmental bronchoprovocation model, with BAL performed at two time points following endobronchial allergen and sham saline challenges. Basal concentrations of TGF-beta 1 were significantly higher in asthmatics than control subjects (median 8.0 versus 5.5 pg/ml, p = 0.027). Following segmental bronchoprovocation, concentrations of TGF-beta 1 at the allergen- and saline-challenged sites were not significantly different after 10 min, (31.3 versus 25.0 pg/ml, p = 0.78), but after 24 h there were significantly higher TGF-beta 1 concentrations at the allergen-challenged sites (46.0 versus 21.5 pg/ml, p = 0.017). We conclude that basal TGF-beta 1 levels in the airways are elevated in atopic asthma and that these levels increase further in response to allergen exposure. These findings are consistent with the hypothesis that TGF-beta 1 is implicated in airway wall remodeling in asthma.

Adult↗
PubMed1997

Airway endothelin levels in asthma: influence of endobronchial allergen challenge and maintenance corticosteroid therapy.

Endothelins (ETs) are 21 amino acid peptides which, in addition to their other properties, are potent bronchoconstrictors. Whilst there is evidence of the involvement of ET in the pathophysiology of chronic asthma, its contribution to the acute allergic response is undefined. To examine this, we have undertaken segmental bronchoprovocation with allergen and saline at separate sites in six atopic asthmatics receiving treatment with bronchodilators only and six atopic asthmatics additionally receiving treatment with inhaled corticosteroids. Each challenged segment was lavaged 10 min after bronchoprovocation and concentrations of immunoreactive ET were measured in bronchoalveolar lavage fluid. In the non-steroid-treated subjects, there were significantly lower ET levels at the allergen-challenged sites compared to the saline-challenged sites (p<0.05). In the steroid-treated subjects, on the other hand, there was no significant difference between the two sites. Levels of ET at the saline-challenged sites were significantly lower in the steroid-treated subjects compared to the non-steroid-treated subjects (p<0.04). These findings do not support the hypothesis that allergen exposure in asthma results in immediate release of endothelin. However, release at later time-points and a role for endothelin in late-phase bronchoconstriction are not excluded.

Adrenal Cortex Hormones↗
PubMed1996

Cytokine production by cell cultures from bronchial subepithelial myofibroblasts.

Myofibroblasts have been previously described beneath the bronchial epithelium and were found to increase in number proportional to the accumulation of extracellular matrix in the bronchial lamina reticularis in asthma. The aim of this study was to assess further the contribution of these structural cells to allergic inflammation in the bronchial mucosa through their cytokine expression. Cell cultures were established from the lamina reticularis of human bronchial biopsies from asthmatic and non-asthmatic subjects. Cytokine secretion was measured by ELISA in supernatants of cultures with or without tumour necrosis factor-alpha (TNF-alpha). The mRNA levels for granulocyte-macrophage colony-stimulating factor (GM-CSF) in the cultures were examined by ribonuclease protection assays (RPAs). Bronchial myofibroblasts grown from bronchial biopsies were capable of producing GM-CSF, interleukin-6 (IL-6), interleukin-8 (IL-8), and stem cell factor (SCF) constitutively. The GM-CSF production by myofibroblasts was significantly increased in response to TNF-alpha simulation with a corresponding increase in GM-CSF mRNA expression. The enhancement of GM-CSF production by TNF-alpha in myofibroblasts was blocked by the inhibition of RNA synthesis. Prednisolone abolished the GM-CSF production. This study provides evidence for the role of bronchial myofibroblasts in the regulation of inflammatory cell recruitment and activation by interaction in the cytokine network in the bronchial mucosa.

Asthma↗
PubMed1996

Cellular and mediator responses twenty-four hours after local endobronchial allergen challenge of asthmatic airways.

The effects of acute allergen exposure on bronchoalveolar lavage cells and mediators and mucosal inflammatory cells were evaluated in 10 subjects with atopic asthma who underwent lavage and biopsy 24 hours after segmental endobronchial allergen challenge. Increased numbers of bronchoalveolar lavage eosinophils were retrieved from the allergen-challenged sites compared with the saline-challenged sites (mean 21.4 vs 1.5 x 10(3) cells/ml; p < 0.02). Numbers of neutrophils and proportions of CD4+, CD8+, CD25+, and HLA-DR+ T cells were similar at the saline- and allergen-challenged sites. In contrast to the bronchoalveolar lavage findings, eosinophil numbers were not increased in the bronchial submucosa or epithelium. There was also no significant difference in neutrophils, mast cells, CD3+, CD4+, or CD8+ T cells in the submucosa after allergen challenge, but the number of activated (CD25+) T lymphocytes in the mucosa did increase after allergen challenge. Allergen challenge did not induce any significant change in endothelial expression of P-selectin, E-selectin, intercellular adhesion molecule-1, or vascular cell adhesion molecule-1. CD11a+ and very late antigen-4+ cell numbers were similar in the saline- and allergen-challenged sites. This study suggests that in patients with very mild asthma, local allergen challenge induces persistent bronchoalveolar lavage eosinophilia, but the recruitment process seems to have diminished or ceased by 24 hours.

Adult↗
PubMed1996

Pathology of rhinitis and bronchial asthma.

Studies of the pathology of rhinitis and asthma have identified similarities and differences between these two clinical conditions. With regard to symptoms, both the nose and the lower airways respond to neural stimulation by irritant substances, but a major difference is that engorgement of the capacitance vessels is the main cause of nasal obstruction in rhinitis, while muscle constriction is the major determinant of lower airway narrowing. There are also similarities and differences with respect to the role of inflammatory cells. In both conditions there is evidence of allergen-induced mast cell activation, with production of an array of mediators (some mast cell-derived and others originating from a variety of other cell types). Eosinophilia is also characteristic of both diseases--it is prominent even in mild forms of asthma, but is low in pollen-sensitive rhinitics outside of the season. T-cell activation and production of cytokines plays an important role in the development and maintenance of allergic disease, but the level of T-cell activation may differ between asthma and rhinitis. Further research into differences in cellular activity and response to treatment between these two diseases may help define factors which will determine whether atopic disease is expressed in the upper, lower, or both parts of the respiratory tract.

Asthma↗
PubMed1996

Histamine and the nasal vasculature: the influence of H1 and H2-histamine receptor antagonism.

The aim was to determine the effect of H1- and H2-receptor blockade on histamine-induced changes in nasal airways resistance and lavage protein concentrations. Normal subjects were pretreated with oral cetirizine or ranitidine in a double-blind and randomized manner. Measurements of the concentration of total protein and albumin in nasal lavage fluid together with nasal airway resistance were made before and after challenge. Any effect of treatment was assessed by comparing the areas under the time-response curves. In all nine subjects available for analysis histamine caused an immediate increase in all measurements. Ranitidine reduced the maximum increase in nasal airway resistance, but this effect was significant only in combination with certirizine. The increase in lavage total protein and albumin concentrations was almost completely abolished by cetirizine, whereas ranitidine had less effect. We conclude that the histamine H1-receptor has the greatest effect on changes in nasal vascular permeability induced by topical histamine, whereas the H2-receptor has the greatest effect on nasal obstruction.

Adult↗
PubMed1996

Effect of natural allergen exposure during the grass pollen season on airways inflammatory cells and asthma symptoms.

BACKGROUND: Bronchial challenge with allergen causes a specific form of airways inflammation consisting of an influx of neutrophils, eosinophils, and T cells. Because the relevance of the challenge model to clinical asthma is uncertain, the cellular changes that occur in the lungs of asthmatic subjects during natural seasonal allergen exposure were investigated. METHODS: Seventeen grass pollen sensitive asthmatic subjects with previously reported seasonal exacerbations of asthma kept records of symptoms and underwent fibreoptic bronchoscopy with bronchoalveolar lavage (BAL) and endobronchial biopsy before and during the peak of the grass pollen season. The BAL cells were analysed for differential cell counts and by flow cytometry for T cell subsets and surface activation markers. The biopsy samples were processed into glycol methacrylate resin and immunohistochemical analysis was performed for mast cells, activated eosinophils, T cells and interleukin 4 (IL-4), a cytokine with a pivotal role in allergen-induced inflammation. RESULTS: In the pollen season there was an increase in T lymphocyte activation in the BAL fluid as identified by increased expression of interleukin 2 receptor (IL-2R). In the submucosa these changes were paralleled by an increase in CD4+ T cells. By contrast, the numbers of metachromatic cells in BAL fluid staining with toluidine blue were reduced, possibly because of degranulation following allergen stimulation. In keeping with mast cell activation, the number of mucosal mast cells staining for secreted IL-4 increased during the season. In comparison with the period shortly before the onset of the season, all but two subjects experienced an asthma exacerbation which followed the rise in pollen counts but, compared with the period preceding the first bronchoscopic examination, asthma symptoms were not increased during the pollen season. CONCLUSIONS: The data suggest that natural allergen exposure, leading to a clinical exacerbation of asthma, may induce an inflammatory response involving T cells, mast cells and eosinophils. The relationship between allergen exposure, cellular infiltration and activation, and clinical symptoms appears to be complex, with factors other than allergen also contributing to asthmatic activity.

Adult↗
PubMed1996

Effect of thromboxane A2-receptor antagonist on bradykinin-induced bronchoconstriction in asthma.

The role of the thromboxane A2 (TxA2) receptor in bradykinin-induced bronchial responses was investigated in this study by using a selective and potent TxA2-receptor antagonist BAY u 3405. Eleven asthmatic subjects were randomized to receive 50 mg of BAY u 3405 or matched placebo in a crossover and double-blind fashion. Ninety minutes after dosing, serum was taken for drug assay, and subjects underwent provocation with bradykinin or prostaglandin D2 (PGD2) to determine bronchial responsiveness [provocative concentration of agonist required to produce a 20% fall in forced expiratory volume in 1 s from the postdiluent baseline (PC20)]. Pretreatment with BAY u 3405 caused a twofold doubling-dilution reduction in bronchial reactivity to PGD2; the geometric mean PC20 values were 0.132 (0.015-0.871) and 0.034 (0.008-0.095) mg/ml, respectively, for active and placebo days (P = 0.001). There was, however, no significant difference in PC20 values for bradykinin between active and placebo treatment days. We have demonstrated that BAY u 3405 caused a significant inhibition of bronchconstriction induced by inhaled PGD2 but had no influence on bronchial responsiveness to inhaled bradykinin. This study suggests therefore that TxA2 receptors do not play a role in bradykinin-induced bronchoconstriction in asthma.

Adult↗