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Biomedical subjects

A J Frew

Publications and source records attributed to A J Frew.

At least 73 records · Page 4Linked to original sources
PubMed1997

Release of RANTES, MIP-1 alpha, and MCP-1 into asthmatic airways following endobronchial allergen challenge.

We have investigated the presence of regulated on activation, normal T-cell expressed and probably secreted (RANTES), macrophage inflammatory peptide-1 alpha (MIP-1 alpha), and macrophage chemotactic peptide (MCP-1) in the bronchoalveolar lavage fluid (BALF) obtained from normal (n = 7) and stable asthmatic subjects (n = 8), and studied their kinetic release into asthmatic airways following endobronchial allergen challenge (n = 18). Measurements of RANTES, MIP-1 alpha, and MCP-1 in 10 times (10x) concentrated BALF showed that these three chemokines were present in both normal controls and stable asthmatic patients, but no significant difference between the two groups was found in the levels of the three chemokines. However, at 4 h after allergen challenge, BALF levels of RANTES, MIP-1 alpha, and MCP-1 were significantly increased in fluid obtained from the allergen-challenge site when compared with the saline-challenge control site (median: 175 pg/ml versus 11.5 pg/ml, 258 pg/ml versus 88 pg/ml, and 900 pg/ml versus 450 pg/ml, respectively). At 24 h, levels of the three chemokines returned to baseline values. To investigate whether cells in BALF obtained 4 h after allergen exposure release chemokines, they were cultured for 24 h. BALF cells from the allergen site released more RANTES and MCP-1 than those from the saline site, but released similar amounts of MIP-1 alpha. These findings suggest that RANTES, MIP-1 alpha, and MCP-1 may regulate cell trafficking in asthma in response to allergen exposure.

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↗
PubMed1997

Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebo-controlled trial.

OBJECTIVES: To assess the efficacy of specific immunotherapy with standardized cat dander extract, using objective endpoints and simulated 'natural' exposure to cats. DESIGN: Double-blind, randomized, placebo-controlled study carried out at a UK Allergy research clinic. SUBJECTS: Twenty-eight patients with moderate to severe allergic rhinoconjunctivitis with asthma due to cat allergy. Subjects were stratified for cat sensitivity, cat ownership and asthma, and the groups were well matched for all relevant parameters. MAIN OUTCOME MEASURES: Symptom scores and peak flow rate during and after exposure to cats in a cat-room. Skin tests and conjunctival provocation thresholds. RESULTS: The actively treated group showed a marked reduction in symptoms during the cat exposure (mean score 61.6-17.1; P < 0.001) with no change in the placebo group (64.7 vs 62.1). The active group also showed a reduced peak flow response to cat exposure (mean fall of 85 L/min pretreatment, 29 L/min after treatment, P < 0.005) as well as reductions in conjunctival provocation sensitivity, skin sensitivity to cat extract and skin sensitivity to house dust mite (D.pteronyssinus). Skin reactivity to histamine and codeine were unaltered. No significant adverse reactions were encountered. CONCLUSIONS: Specific immunotherapy seems to be an effective treatment for cat allergy. Allergy to cats is common and often poorly controlled on conventional pharmacotherapy. Although cat allergy has not traditionally been considered as a valid indication for immunotherapy in the UK, it should now be considered as a legitimate treatment, especially for those who are unable to avoid exposure.

Adult↗
PubMed1996

The immunology of respiratory allergies.

The main function of the respiratory tract is to provide a large surface area of thin epithelium for gas exchange. At the same time, this exposed surface and the conducting airways have to be defended against airborne irritants and infectious agents. The principal defence is the barrier formed by airway mucus and the mucociliary escalator. Agents which penetrate the initial defences may be destroyed by phagocytic cells, and may initiate an immune response. Respiratory allergy results when airborne allergens penetrate these defences and elicit and unhelpful immunological response. The nature of the airway immune response depends on the nature of the allergen, the antigen-processing pathway, and the microenvironment which dictates the phenotype of available T lymphocytes. Most allergens elicit IgE antibodies which then bind to mast cells and, when cross-linked, the mast cell releases inflammatory mediators which cause bronchospasm and mucus formation. Some chemical allergens appear able to trigger this pathway without involving IgE. In both cases, other inflammatory cells, especially eosinophils, are then recruited. These cells appear to be responsible for the epithelial damage and increased airways reactivity that characterise asthma. Similar histological patterns are found in atopic asthma, non-atopic asthma, occupational asthma due to low molecular weight chemicals and even in the reactive airways dysfunction syndrome (RADS)/irritant-induced asthma syndrome. Allergic airway inflammation and clinical asthma appear to be common histological and clinical consequences of a variety of specific and non-specific insults to the airways epithelium, airways mast cells and airways T lymphocytes.

Allergens↗
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

Distribution and determinants of personal exposure to nitrogen dioxide in school children.

OBJECTIVES: To assess the distribution of personal exposures to nitrogen dioxide (NO2) in school children, and to investigate factors that might influence personal exposure. METHODS: NO2 exposures were assessed by use of passive diffusion tubes for 46 children aged 9-11 years, selected from two Southampton schools. The tubes were worn for seven days, and parallel measurements were made with static samplers in the child's kitchen, living room, classroom, and playground. Information about potential exposures was collected by questionnaire. RESULTS: Personal exposures to NO2, averaged over seven days, ranged from 11 to 257 micrograms/m3 (6 to 137 ppb) with a geometric mean of 36 micrograms/m3 (19 ppb). Exposures correlated with concentrations of NO2 recorded in the home, but the relation was far from exact. Factors associated with increased personal exposure included the use of gas appliances in the home, living with one or more smokers, and travel to school by means other than a car. However, together these variables only explained a small part of the variation in personal exposures. CONCLUSIONS: These findings reinforce the need for personal monitoring of exposure in studies investigating potential health effects of NO2 in children.

Child↗
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

Cellular infiltration of the airways in asthma of varying severity.

We have tested the hypothesis that airway infiltration by inflammatory cells reflects the severity of asthma by comparing the inflammatory cell infiltrates in fatal severe asthma and in subjects with mild to moderate asthma who died of unrelated causes. Sections of lung tissue from 25 fatal asthma cases and eight asthmatics who died of unrelated causes were immunostained by monoclonal antibodies (mAbs) using streptavidin-biotin peroxidase technique. The following cells were identified: mast cells (AA1:tryptase), eosinophils (EG1:stored cationic protein and EG2: secretory form of cationic protein), monocytes/macrophages (CD68), neutrophils (elastase), CD3+ and CD8+ T cells (CD3 polyclonal Ab and CD8+ mAb, respectively). Positive cells were counted in the epithelium and airway wall. The airways were divided into two groups: larger airways with internal perimeter (Pi) > 2 mm and smaller airways with Pi < 2 mm. All airways together were studied first, followed by larger and smaller airways examined separately. The numbers of intraepithelial CD3+ T cells were significantly lower in fatal asthma than in mild-moderate asthma both when all airways were considered (0.35 versus 0.86 cells/mm, p = 0.034) and in the larger airways alone (0.08 versus 1.05 cells/mm, p = 0.039). The numbers of EG1- and EG2-positive eosinophils infiltrating the airway wall of the larger airways were greater in fatal asthma than in mild-moderate asthma (78.2 versus 22.8 cells/mm2, p = 0.012 and 138.1 versus 31.7 cells/mm2, p = 0.022). In the smaller airways no significant difference was found between the two groups. We conclude that in fatal asthma there is a redistribution of CD3+ T cells away from the epithelium and proximal enhancement of the eosinophil inflammatory infiltrate. These findings have implications for the pathophysiology of asthma that results in death.

Adolescent↗
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

Immunopathology of fatal soybean dust-induced asthma.

A hypothesis was postulated that the characteristic clinical course of fatal soybean asthma may be reflected by specific immunopathological findings. Seven cases of fatal soybean dust-induced asthma from Barcelona, Spain were compared with 25 fatal asthma cases from New Zealand. Sections of lung tissue were stained by monoclonal antibodies using standard streptavidin-biotin peroxidase technique. The following cell types were identified: mast cells, "activated" eosinophils, neutrophils, monocytes/macrophages, CD3+ T-cells and CD8+ T-cells. The positively staining cells were counted in the epithelium and the submucosa and their numbers expressed per mm and mm2, respectively. The airways were divided into larger (internal perimeter (Pi) > 2 mm) and smaller (Pi < 2 mm). Firstly, all airways were studied together; and subsequently, larger and smaller airways were studied separately. Differences in the numbers of mast cells, eosinophils, neutrophils and monocytes/macrophages between the two groups were not significant. The numbers of CD3+ and CD8+ T-cells were significantly reduced in fatal soybean asthma when all airways were taken together. In larger airways, the difference was not significant in the epithelium, but was significant in the submucosa for CD3+ cells. CD8+ cells were significantly reduced in fatal soybean asthma both in the epithelium and the submucosa. The cell counts in smaller airways were not significantly different either in the epithelium or in the submucosa for CD3+ cells. The numbers of CD8+ cells were not different in the epithelium, but were significantly reduced in the submucosa of fatal soybean asthma cases. We conclude that the numbers of CD3+ and CD8+ T-cells are substantially reduced in fatal soybean asthma. These data together with the clinical features of the fatal attack suggest a different mechanism(s) from that described for most asthma deaths, probably involving anaphylaxis.

Adult↗
PubMed1995

Analysis of Ig VH region genes encoding IgE antibodies in splenic B lymphocytes of a patient with asthma.

An atopic patient with hypersensitivity against house dust mite died as a result of an asthmatic attack. A portion of the spleen was obtained and was used to analyze the spectrum of Ig heavy chain V regions involved in encoding IgE Abs. A nested PCR technique generated 14 cloned VH sequences that had distinct CDR3 regions; 5 of 14 were derived from the minor VH5 family, and the remainder derived from the larger families, VH3 (6 of 14) and VH4 (3 of 14). One of the VH3-derived sequences was present as a repeated sequence in three clones. A control PCR with the same VH primers in combination with JH primers yielded only 1 of 13 sequences from VH5, indicating preferential VH5 usage only for IgE. Analysis of VH5-C epsilon sequences revealed usage of a single gene, DP73, with extensive mutations and several "hot spots" containing common replacement amino acids. However, there was no concentration of replacement mutations in the CDRs, which conventionally would indicate a role for Ag selection. The VH3 and VH4 genes in combination with C epsilon also harbored extensive somatic mutations. From these findings in splenic B lymphocytes, and those of a previous study of blood lymphocytes, it seems that preferential usage of VH5 genes and extensive somatic hypermutation are characteristic of B cells synthesizing IgE in patients with allergic disease.

Adult↗