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Biomedical subjects

S T Holgate

Publications and source records attributed to S T Holgate.

At least 307 records · Page 17Linked to original sources
PubMed1995

Bloodspot cortisol in mild asthma: the effect of inhaled corticosteroids.

Bloodspot cortisol, where finger pricked blood is applied to blotting paper, is suitable for repeated measurements in the home environment. The use of bloodspot cortisol measurements in children with asthma and the effect of inhaled corticosteroids on daytime cortisol concentrations were assessed. Twenty children with mild asthma were randomised to receive double blind either placebo or beclomethasone dipropionate 200 micrograms twice daily. Blood was taken by finger prick at home on waking, and treatment administered. Blood was then taken one hour after treatment, at lunchtime, and in the evening. The area under the curve (AUC) for the four time points was calculated as a composite index of daytime cortisol. Mean (SEM) bloodspot cortisols fell progressively over the day from 199.2 (15.6) nmol/l to 58.4 (8.9) nmol/l. Cortisol in the group treated with beclomethasone dipropionate was lower at all time points, but was significant only after treatment (mean (SEM) 120.9 (14.3) v 177.5 (21.0) nmol/l) and at lunchtime (mean (SEM) 82.7 (12.4) v 128.9 (12.6) nmol/l). AUC for the beclomethasone dipropionate treated group was also significantly decreased (mean (SEM) 317 (31.4) v 446 (29.7)). Beclomethasone dipropionate at a dose of 400 micrograms/day significantly suppresses the daytime cortisol profile.

Administration, Inhalation↗
PubMed1995

Peak flow based asthma self-management: a randomised controlled study in general practice. British Thoracic Society Research Committee.

BACKGROUND: Peak flow based asthma self-management plans have been strongly advocated in consensus statements, but convincing evidence for the effectiveness of this approach has been largely lacking. METHODS: A randomised controlled trial was conducted in 25 general practices comparing an asthma self-management programme based on home peak flow monitoring and surgery review by a general practitioner or practice nurse with a programme of planned visits for surgery review only over a six month period. RESULTS: Seventy two subjects (33 in the self-management group and 39 in the planned visit group) completed the study protocol, but diary card data for at least three months were available on a total of 84 (39 in the self-management group and 45 in the planned visit group). Teaching self-management took longer than the planned visit review. In the self-management group home peak flow monitoring was felt to be useful by doctors and patients in 28 (85%) and 27 (82%) cases, respectively. There were no between group differences during the study period in terms of lung function, symptoms, quality of life, and prescribing costs. Only within the self-management group were improvements noted in disturbance of daily activities and quality of life. Possible explanations for these negative results include small numbers of subjects, the mild nature of their asthma, and inappropriate self-management strategies for such patients. CONCLUSIONS: Rigid adherence to long term daily peak flow measurement in the management of mild asthma in general practice does not appear to produce large changes in outcomes. Self-management and the use of prescribed peak flow meters need to be tailored to individual circumstances.

Adolescent↗
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

Growth of prepubertal children with mild asthma treated with inhaled beclomethasone dipropionate.

Poorly controlled severe asthma can lead to growth impairment in childhood. In children with mild asthma, it is less clear whether treatment influences growth or adrenal function. We determined in a randomized, double-blind, placebo-controlled, community-based study, the effect of inhaled beclomethasone dipropionate (BDP) 400 micrograms/day for 7 mo on the linear growth and adrenal function of 94 children 7 to 9 yr of age. Height was measured at least monthly during treatment, and adrenal function assessed by overnight urinary cortisol at baseline and after 3 and 6 mo of treatment. Mean regressed daily growth was significantly decreased during the treatment period in the BDP-treated group, 0.79 versus 1.14 mm/wk (difference 0.35 mm/wk; 95% CI -0.46 to -0.25; p < 0.0001). At the end of the 7 mo, the BDP-treated children had grown significantly less than the children on placebo: mean of 2.66 versus 3.66 cm (difference 1.0 cm; 95% CI -1.36 to -0.64 cm; p < 0.0001). Growth was significantly decreased in both males and females. During a washout period of 4 mo, there was no significant catch-up growth. BDP had no effect on overnight urinary cortisol production. BDP at a dose taken by many children significantly decreases statural growth in children with mild asthma, and this effect is unlikely to be mediated through the hypothalamo-pituitary-adrenal axis.

Administration, Inhalation↗
PubMed1995

Cytokine immunoreactivity in seasonal rhinitis: regulation by a topical corticosteroid.

Seasonal allergic rhinitis is characterized by the development of nasal mucosal inflammation in response to natural allergen exposure, and is prevented by the administration of topical corticosteroids. Interleukin-4 (IL-4), IL-5, and IL-6 may have important roles in this process, and in vitro the gene transcription for each of these cytokines is inhibited by corticosteroids. In this study we have therefore investigated the effect of seasonal allergen exposure on the expression of immunoreactivity for IL-4, IL-5, and IL-6 in nasal mucosal biopsies, and the effect of regular prophylactic treatment with the topical corticosteroid, fluticasone propionate. Following a nasal mucosal biopsy out of season, patients were randomized double-blind to receive 6 wk of treatment during the pollen season with either topical fluticasone nasal spray (200 micrograms daily) or matching placebo. Each subject underwent a repeat nasal biopsy at the end of the 6-wk treatment period. Seasonal increases in epithelial eosinophils (p = 0.046), submucosal eosinophils (p = 0.001), and epithelial mast cells (p = 0.055) occurred in the placebo--but not the fluticasone-treated patients. Submucosal mast cell numbers did not change in either group. Immunoreactivity for IL-4 and IL-6 was localized predominantly to mast cells while IL-5 was found in both mast cells and eosinophils. Numbers of IL-4+ cells in the nasal submucosa were significantly suppressed by treatment with fluticasone (p = 0.0003 for monoclonal antibody [mAb] 3H4, p = 0.041 for mAb 4D9). In contrast, fluticasone treatment failed to influence the number of IL-5 and IL-6 immunoreactive cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intranasal↗
PubMed1995

Release of mast-cell-derived mediators after endobronchial adenosine challenge in asthma.

Preformed and newly generated mediators released from airway mast cells may play a role in adenosine-induced bronchoconstriction. To investigate the possible role of mast-cell-derived mediator release in mediating bronchoconstriction induced by adenosine 5'-monophosphate (AMP), we have examined the fluid obtained by bronchoalveolar lavage for inflammatory mediators and markers of airway permeability immediately after instillation of AMP directly into an airway segment of 10 asthmatic subjects. Eight subjects completed the protocol. When compared with the saline-challenged segment, the response to endobronchial stimulation with AMP was characterized by a prompt reduction in airway caliber paralleled by a significant rise in PGD2, histamine, and tryptase levels in the lavage fluid. After AMP challenge, the median (range) concentration for PGD2 increased from 36 to 205 pg/ml (p = 0.006), for histamine from 184 to 433 pg/ml (p = 0.018), and for tryptase from 0.30 to 0.54 ng/ml (p = 0.013). In addition, a small but significant rise in albumin levels (from 27.8 to 36.1 micrograms/ml; p = 0.031) was detected after endobronchial challenge with AMP. These findings indicate that adenosine-induced responses may be initiated by the acute release of mast-cell-derived mediators, including PGD2, histamine, and tryptase.

Adenosine Monophosphate↗
PubMed1995

The influence of increased bronchial responsiveness, atopy, and serum IgE on decline in FEV1. A longitudinal study in the elderly.

We have performed a 4-yr prospective survey of the association of allergen skin test positivity, total serum immunoglobulin E (IgE), and bronchial responsiveness to methacholine, with longitudinal decline in FEV1, in subjects over 65 yr of age. In 1987, 324 subjects completed a respiratory questionnaire, and underwent measurement of FEV1 and FVC, methacholine challenge, skin prick testing (to Dermatophagoides pteronyssinus, cat fur, mixed grasses, and Aspergillus fumigatus) and estimation of total serum IgE. After an interval of 4 yr, 212 subjects were reexamined. The mean annual decline in FEV1 was significantly higher in males than in females, but was not significantly influenced by smoking habits defined at the start of the study. The relation of atopy (skin test reaction to allergen > or = 3 mm greater than saline control), increased bronchial responsiveness (PD20FEV1 < or = 6.4 mumoles methacholine) and serum IgE > 80 IU/ml, to annual decline in FEV1 was examined for each risk factor individually with adjustment for age, sex, height, and initial FEV1, by multiple linear regression. Both atopy and bronchial responsiveness were significantly associated with accelerated decline in FEV1. Elevated IgE was correlated with faster FEV1 decline in subjects who were current smokers at the start of the study. In a multiple regression model examining the mutually adjusted associations of all relevant variables with annual decline in FEV1, male sex was the most important predictor (B = 38.6 ml/yr, 95% Cl = 4.3, 72.9). Increased bronchial responsiveness also tended to be associated with accelerated decline in FEV1. In further analyses incorporating the same variables, but restricted to specific smoking categories, age was the only significant factor in the never-smokers, whereas both atopy (B = 44.5 ml/yr, 95% Cl = 3.8, 85.3) and increased bronchial responsiveness (B = 43.5 ml/yr, 95% Cl = 4.6, 82.3) were significant predictors of accelerated FEV1 decline in former and current smokers combined.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects.

Human rhinoviruses (HRV) cause the majority of common colds and are etiologically linked with changes in lower airways physiology and asthma exacerbations. We hypothesized that changes in bronchial mucosal inflammatory cell populations may be responsible for HRV-induced changes in airway reactivity. We examined bronchial mucosal biopsies during experimental infections with HRV serotype 16 and measured changes in histamine reactivity. Seventeen adult volunteers (six atopic asthmatics) had baseline measurements of histamine reactivity and fiberoptic bronchoscopic biopsies, followed 2 wk later by viral inoculation. Further bronchial biopsies were taken on Day 4 of the infection and 6 to 10 wk later. Mast cells, eosinophils, lymphocytes, and neutrophils were quantified by immunohistochemical techniques. Infection was documented by viral culture, seroconversion, and symptoms. An increase in histamine responsiveness during the cold (p = 0.048) was accompanied by increases in submucosal lymphocytes (p = 0.050). There was a subsequent decrease in submucosal and epithelial lymphocytes in convalescence (p = 0.028; p = 0.030). There was an increase in epithelial eosinophils with the cold (p = 0.042), and in asthmatics this appeared to persist into convalescence. A peripheral blood lymphopenia correlated with increased responsiveness (r = 0.062, p = 0.014). Rhinoviral colds are associated with a bronchial mucosal lymphocytic and eosinophilic infiltrate that may be related to changes in airway responsiveness and asthma exacerbations.

Adult↗
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

Do lower respiratory tract infections in early childhood cause chronic obstructive pulmonary disease?

The hypothesis that lower respiratory tract infections (LRTI) in early childhood lead to chronic obstructive pulmonary disease (COPD) in late adult life has been difficult to test. However, a unique opportunity arose when records were discovered in the counties of Hertfordshire and Derbyshire, England, that contained information about childhood LRTI recorded 60 to 70 years ago. The lung function of some men still living in these counties was examined. In Hertfordshire men, bronchitis or pneumonia in infancy was associated with reduced mean FEV1, adjusted for age and height. In Derbyshire men, pneumonia before 2 yr of age was associated with a large and highly significant reduction in mean FEV1, adjusted for age and height. These findings were independent of smoking and social class. These data support a causal relationship between LRTI in early life and subsequent COPD.

Adult↗
PubMed1995

Augmentation of permeability in the bronchial epithelium by the house dust mite allergen Der p1.

Sequence analyses have revealed the existence of homology between certain aeroallergens and proteolytic enzymes. This homology can be expressed functionally, but its significance to airway pathophysiology is unknown. Studies with Madin-Darby canine kidney cells and canine tracheal epithelial cells grown on plastic substrata or matrix proteins suggest that Der p1, a major allergen from the house dust mite Dermatophagoides pteronyssinus and a cysteine proteinase, or the unfractionated growth medium extract (SGME) from which it was purified, are both capable of causing cell detachment. The ability of both agents to produce functional changes in the barrier function of the epithelium was further demonstrated using isolated bovine airway preparations. Over a 3-h duration, both Der p1 and SGME elicited significant increases in the permeability of isolated sheets of bronchial mucosa to serum albumin. Exposure of isolated bronchial segments to luminally applied solutions of Der p1 resulted in histologic evidence of epithelial injury. Neither Der p1 nor SGME was active in these experimental systems unless chemically reduced, suggesting that the effect was initiated by cysteine proteinase activity. Similar augmentation of mucosal permeability and tissue injury was produced by bovine trypsin and collagenase from Clostridium histolyticum. In both the isolated mucosal sheet model and in cultured cells, the actions of Der p1 or SGME were associated with relatively little cytolysis, suggesting a specific action of the reagents on cell attachment. These results demonstrate a new functional activity of Der p1 that may be germane to the processes of allergen presentation, inflammatory cell activation, and chronic tissue injury.

Animals↗
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↗
PubMed1995

Early identification of interleukin-16 (lymphocyte chemoattractant factor) and macrophage inflammatory protein 1 alpha (MIP1 alpha) in bronchoalveolar lavage fluid of antigen-challenged asthmatics.

Accumulation of CD4+ interleukin (IL)-2R+ lymphocytes in the airways of asthmatics is generally attributed to the presence of chemoattractant cytokines. The precise mechanism for the initiation of the earliest CD4+ lymphocyte infiltration and activation is unknown. In this study, we describe for the first time the presence of lymphocyte chemoattractant activity in the bronchoalveolar lavage (BAL) fluid obtained from asthmatics 6 h after antigen challenge. The majority of the chemoattractant activity at this early time point is represented by IL-16 (lymphocyte chemoattractant factor), a CD4+ cell-specific chemoattractant and growth factor. In addition to IL-16, macrophage inflammatory protein 1 alpha (MIP1 alpha) chemotactic bioactivity was detected in significant levels. While IL-16, MIP1 alpha, and IL-8 were all identified by enzyme-linked immunosorbent assay, the great majority of the lymphocyte chemoattractant activity in the BAL fluid after antigen challenge is attributable to IL-16 and MIP1 alpha. There were no detectable levels of IL-16 nor MIP1 alpha in BAL fluid of antigen-challenged normal subjects nor atopic nonasthmatics nor in saline-challenged lobes from the asthmatics. The identification of multiple lymphocyte chemoattractants early after antigen challenge suggests a complex cellular, as well as chemoattractant cytokine, profile in initiating the CD4+ T cell-mediated inflammatory process that is specific for the atopic asthmatic phenotype.

Adult↗
PubMed1995

The effects of theophylline on mucosal inflammation in asthmatic airways: biopsy results.

Theophylline, a nonspecific phosphodiesterase inhibitor, has only recently been reconsidered as a potential anti-inflammatory drug. Its ability to inhibit late asthmatic responses has pointed to possible inhibition of mechanisms regulating the influx and activity of inflammatory cells into the airways. Increasing evidence points to an anti-inflammatory action of theophylline at doses lower than those necessary for a bronchodilator effect. Withdrawal of theophylline from regular treatment results in an increase both in CD4+ and CD8+ T-cells in the bronchial mucosa and a concomitant decrease in the blood, suggesting that theophylline prevents T-cell trafficking from blood into the airways. Furthermore, pretreatment with theophylline significantly attenuates the influx of eosinophils into the airways associated with an allergen-induced late asthmatic response. In keeping with these observations, in a double-blind, placebo-controlled trial involving mild to moderately severe atopic asthmatics, treatment with theophylline resulted in a significant reduction in the numbers of epithelial CD8+ T-cells. In addition, the numbers of cells containing cytokines, interleukin 4 and 5 (IL-4 and IL-5), decreased in the theophylline-treated group and increased in the placebo-treated group, with the difference between the changes being significant. It would, therefore, appear that theophylline may contribute to asthma control due to its ability to reduce the suppressor/cytotoxic T-cells and cytokines which are relevant to allergic mucosal responses.

Anti-Inflammatory Agents, Non-Steroidal↗