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Biomedical subjects

A E Redington

Publications and source records attributed to A E Redington.

At least 37 records · Page 2Linked to original sources
PubMed1999

Airway endothelin levels in asthma: influence of endobronchial hypertonic saline challenge.

BACKGROUND: The pathophysiology of exercise-induced asthma is not well understood. Hypertonicity of the airway lining fluid resulting from loss of water due to hyperventilation is considered to play a role, but the precise mechanism by which hypertonicity can induce bronchoconstriction is unknown. Peptides of the endothelin (ET) family have potent smooth muscle contractile properties, and have been linked to airway narrowing in stable asthma. We postulated that ET release may contribute to the acute bronchoconstrictor response induced by a hypertonic stimulus. METHODS: Seven male asthmatic subjects underwent local endobronchial challenge with hypertonic (3.6%) saline and, as a control, isotonic (0.9%) saline aerosols in separate bronchopulmonary segments. Bronchoalveolar lavage (BAL) was performed at both sites during the phase of immediate bronchoconstriction. Concentrations of immunoreactive ET and of the mast cell products, histamine, tryptase and prostaglandin D2, in BAL fluid were measured. RESULTS: Concentrations of ET in BAL fluid from the hypertonic saline-challenged sites were significantly lower than those in BAL fluid from sites exposed to isotonic saline (0.19 [0.11-1.24] fmol/mL vs. 0.40 [0.20-2.36] fmol/mL, P<0.05). Concentrations of histamine, tryptase, and prostaglandin D2 did not differ significantly between the two sites. CONCLUSIONS: These findings do not support the hypothesis that ET release within the airway lumen is involved in the bronchoconstrictor response induced by hypertonic saline.

Adult↗
PubMed1998

Co-localization of immunoreactive transforming growth factor-beta 1 and decorin in bronchial biopsies from asthmatic and normal subjects.

Airway wall remodelling is an established pathological feature of asthma but its causes are not well understood. One cytokine of potential relevance is transforming growth factor-beta1 (TGF-beta 1). The immunolocalization of TGF-beta 1 and of its small binding proteoglycan decorin have been examined in the airways of normal subjects and atopic asthmatics. Bronchial biopsy specimens were obtained by fibreoptic bronchoscopy, processed into glycolmethacrylate resin, and stained immunohistochemically using specific antibodies. Immunoreactive TGF-beta 1 was principally localized extracellularly in association with subepithelial connective tissue. Some staining of bronchial epithelial cells was also evident, but otherwise there was little intracellular staining. The overall pattern of immunohistochemical staining was indistinguishable in biopsy specimens from asthmatic and control subjects. Comparison of adjacent sections demonstrated the co-localization of immunoreactivity for TGF-beta 1 and decorin in the mucosa. It is concluded that immunoreactive TGF-beta 1 in human airways is principally extracellular and that matrix-associated TGF-beta 1 is likely to be bound at least in part to decorin. This interaction may provide a reservoir of TGF-beta 1 that can be released in an active form in response to appropriate stimuli.

Adult↗
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↗
PubMed1998

Long-acting inhaled beta 2-agonists in the management of asthma: recent advances and current recommendations.

Salmeterol and formoterol belong to a new class of inhaled beta 2-agonists with a prolonged duration of action. At the time these agents were introduced, there was uncertainty regarding the safety of beta 2-agonist therapy in asthma and concern that they might lead to a deterioration in asthma control. Recent studies, in contrast, have demonstrated both their safety and therapeutic efficacy. The aims of this review are to highlight these new developments and to consider the place of these long-acting beta 2-agonists in asthma management strategies.

Adrenergic beta-Agonists↗
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

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

Safety aspects of local endobronchial allergen challenge in asthmatic patients.

Local endobronchial allergen challenge is being increasingly used to investigate the role of allergic inflammation in asthma. However, little information is available about the safety of this procedure and the changes induced in airway physiology. BAL and biopsy were performed at 10 min and at 4 to 6 h, or 24 h after segmental allergen challenge in 49 patients with atopic asthma. Two hours after challenge, FEV1 was reduced from 97.6 +/- 13.9 (mean +/- SD) to 83.4 +/- 21.7% predicted. FEV1 remained reduced at 4 to 6 h (87.7 +/- 20.4%), but it had nearly returned to baseline by 24 h (93.2 +/- 14.0%). When endobronchial challenge was combined with BAL and biopsy, the initial fall in FEV1 was slightly greater (from 101.8 +/- 14.2 to 78.5 +/- 13.6%). Bronchial responsiveness to methacholine was measured in 10 subjects, and it showed a twofold increase 24 h after local challenge and lavage. Significant changes in FEV1 and methacholine PC20 were still detectable 72 h after challenge. Widespread wheezing occurred in 29% of the subjects, but none of the them had to be admitted to hospital. We conclude that local endobronchial allergen challenge, although producing measurable changes in airway physiology, is in general well tolerated and is an acceptable method to investigate airway pathophysiologic processes in patients with mild to moderate asthma.

Adult↗
PubMed1996

Leukocyte recruitment after local endobronchial allergen challenge in asthma. Relationship to procedure and to airway interleukin-8 release.

We have investigated the profile of cellular recruitment into asthmatic airways after allergen and saline exposure and its relationship to interleukin-8 (IL-8) release. Fiberoptic bronchoscopy was used to instill allergen into the middle lobe while the right upper lobe received a sham saline challenge. Bronchoalveolar lavage (BAL) of both sites was performed either 4 or 24 h later. Neutrophil numbers in BAL fluid obtained 4 and 24 h after challenge were 17 and 48 times higher than prechallenge numbers (p < or = 0.001), but there was no statistically significant difference between the numbers of neutrophils at the two sites. In contrast, eosinophil numbers were increased by 6- and 20-fold, respectively, at 4 and 24 h at allergen-challenged as compared with saline-challenged sites (p < 0.005 and p < 0.02, respectively). Baseline concentrations of IL-8 in BAL fluid were undetectable in most cases. Four hours after allergen or saline exposure, BAL fluid IL-8 concentrations were: median, 200 pg/ml; range, 20 to 750 pg/ml and median, 123 pg/ml; range, < 20 to 800 pg/ml, respectively. These declined to 23 pg/ml (range, < 20 to 126 pg/ml) and 43 pg/ml (range < 20 to 130 pg/ml), respectively, 24 h after exposure. There was a significant correlation between neutrophil numbers and IL-8 concentrations 4 h after saline exposure. These findings indicate that neutrophil infiltration is a nonspecific response to the procedure of bronchoscopy and lavage, in contrast to eosinophil recruitment, which is an allergen-specific phenomenon, and it suggests that IL-8 release may be involved in neutrophil recruitment.

Adult↗
PubMed1996

T-cell cytokine profile evaluated at the single cell level in BAL and blood in allergic asthma.

Atopic asthma is characterized by bronchial mucosal inflammation, involving eosinophils, mast cells, and lymphocytes. It has been suggested that the development and maintenance of this allergic inflammation is due to T-lymphocyte activation with predominant production of the cytokines interleukin 4 (IL-4) and IL-5. To address the ability of peripheral blood and bronchoalveolar lavage T-cells to generate IL-2, IL-4, or interferon gamma (IFN-gamma), we have employed a flow cytometric method which permits analysis of cytokine production at the single cell level within 5 h of obtaining cell samples. When stimulated with PMA and ionomycin, there was a greatly increased percentage of IFN-gamma-producing cells among bronchoalveolar lavage (BAL) T-cells from the subjects with asthma (median 74%), compared with atopic and nonatopic controls (35 and 43%, respectively; P>0.01). The proportion of BAL T-cells producing IL-4 was small (median 1.7%, range 0 to 7.8% in the asthmatic group). In all three groups, the proportion of BAL T-cells producing IL-2 or IFN-gamma was increased compared with T-cells from peripheral blood. There was no significant difference between the three groups in the percentage of BAL T-cells producing IL-2, or in the percentage of peripheral blood T-cells producing IFN-gamma, IL-2 or IL-4. These findings indicate that IL-4 production is confined to a relatively small proportion of airway and blood T-cells and that there is selective enhancement of IFN-gamma production by airway T-cells in asthma.

Adult↗
PubMed1996

Dendritic cells in normal and asthmatic airways: expression of the alpha subunit of the high affinity immunoglobulin E receptor (Fc epsilon RI -alpha).

BACKGROUND: Immunoglobulin E (IgE) plays an important role in asthma, with total serum IgE levels closely related to both clinical expression of the disease and airway hyperresponsiveness. IgE binds to a high affinity cell-surface receptor (Fc epsilon RI) which is present on mast cells and which has also recently been demonstrated on cutaneous dendritic cells. If pulmonary dendritic cells were also able to express this receptor, this would have important implications with regard to their potential role in asthma. OBJECTIVES: The aims of the study were to investigate the expression of the alpha subunit of the high affinity IgE receptor (Fc epsilon RI-alpha) in normal and asthmatic airways, and to analyse its cellular provenance with particular emphasis on the dendritic cell. METHODS: Bronchial biopsy specimens were obtained using fibreoptic bronchoscopy from 10 atopic asthmatics and nine non-atopic non-asthmatic control subjects. Specimens were processed into glycolmethacrylate resin and analysed by immunohistochemistry using specific monoclonal antibodies against Fc epsilon RI-alpha, and against tryptase and CD1a, markers for mast cells and dendritic cells, respectively. RESULTS: The numbers of dendritic cells were significantly higher in the airways of asthmatics compared with those of control subjects (P < 0.02). Analysis of sequential sections revealed that the alpha subunit of Fc epsilon RI was localized to both mast cells and dendritic cells. The proportion of dendritic cells expressing Fc epsilon RI-alpha was significantly increased in the asthmatic group (P < 0.003). CONCLUSION: These results support the hypothesis that dendritic cells play an important role in allergic asthma although the functional significance of Fc epsilon RI-alpha expression needs further investigation.

Adult↗
PubMed1995

Endothelin in bronchoalveolar lavage fluid and its relation to airflow obstruction in asthma.

Endothelins (ETs) are a family of peptide mediators that have a number of biological properties, including the ability to act as potent bronchoconstrictors of isolated human airways. To examine the possible involvement of ET in asthma, we have performed fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) on 10 healthy control subjects, 10 patients with atopic asthma treated with bronchodilators alone, and 8 patients with atopic asthma treated with inhaled and/or oral corticosteroids. Endothelin concentrations in BAL fluid were measured by radioimmunoassay and total protein concentrations by a colorimetric method. There was a significant increase in the BAL fluid ET levels in the non-steroid-treated patients with asthma compared with the normal subjects, when expressed either as a concentration (median, 0.30 versus 0.08 pM; p = 0.001) or in relation to total protein (median, 3.02 versus 1.08 pmol/g; p = 0.01). There was, however, no statistically significant difference in ET levels between the steroid-treated patients with asthma, and either of the other two groups. In the non-steroid-treated patients with asthma there was a significant negative correlation between the BAL fluid ET concentration and the % predicted FEV1 (r = -0.71, p = 0.03). This correlation was not significant in the steroid-treated subjects, and no correlation between BAL fluid ET concentrations and bronchial reactivity was found in any of the three groups. These findings are consistent with the hypothesis that ET contributes to the pathophysiology of asthma.

Adrenal Cortex Hormones↗
PubMed1995

15-lipoxygenase immunoreactivity in normal and in asthmatic airways.

Products of the 15-lipoxygenase (15-LO) pathway of arachidonic acid metabolism such as the mono- and di-hydroxyeicosatetraenoic acids (HETEs) may contribute to the pathophysiology of allergic airway inflammation through the recruitment and activation of inflammatory cells and stimulation of glandular secretion. In this study we have examined the expression of 15-LO and its cellular localization in the asthmatic and normal bronchial mucosa. Bronchial mucosal biopsies were obtained by fiberoptic bronchoscopy from 10 patients with symptomatic allergic asthma and six normal control subjects and processed into glycolmethacrylate resin. Sections 2 microns thick were immunostained using a specific rabbit polyclonal antihuman 15-LO antibody. Strong immunoreactivity for 15-LO was present throughout the epithelium in both the asthmatic and the normal subjects, with no difference between the two groups. Cells expressing 15-LO immunoreactivity were also present in the submucosa of both groups, with a significantly greater number present in the asthmatic group (median, 15.3 cells/mm2) than in the normal group (median, 6.9 cells/mm2) (p = 0.01). The majority (85%) of the submucosal 15-LO+ cells were eosinophils. Patchy 15-LO immunoreactivity was also seen in the vascular endothelium in both groups. These findings demonstrated increased 15-LO expression in the bronchial submucosa of asthmatic subjects, and they suggest that 15-LO products in asthma originate from both bronchial epithelium and infiltrating eosinophils.

Adult↗
PubMed1995

Neuropeptide-containing nerves in endobronchial biopsies from asthmatic and nonasthmatic subjects.

The presence and distribution of neuropeptide-containing nerves within endobronchial biopsies has been investigated in symptomatic asthmatics (n = 17) and in asymptomatic nonasthmatic control subjects (n = 17). Biopsies from large airways, obtained under local anesthesia by flexible fiberoptic bronchoscopy, were processed immediately and analyzed for nerves using specific indirect immunofluorescence with antisera to the neural marker protein gene product 9.5 (PGP 9.5) and the neuropeptides vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), and neuropeptide tyrosine (NPY). PGP 9.5-positive nerves were present in all the biopsies from both subject groups, being identified in relationship to epithelium, glands, smooth muscle, and blood vessels. VIP- and NPY-immunoreactive nerves were equally present in the biopsies of both asthmatic and nonasthmatic subjects, being localized to smooth muscle and glands. Using well-substantiated antibodies, no nerves immunofluorescent for SP or CGRP were identified in any of the biopsies of the subjects. In the asthmatic patients, there were no significant correlations between the PGP 9.5, VIP, or NPY immunofluorescence scores and the resting spirometric values (FEV1) or the level of nonspecific bronchial responsiveness, as assessed by the provocative concentration of methacholine required to produce a 20% fall in FEV1. To verify the single biopsy findings, two further studies were undertaken, one in which biopsies were stained from two airway sites (proximal and distal) and a second in which the findings in carinal specimens obtained using biopsy forceps from freshly resected lung tissue were compared with those in a surrounding area of tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗