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Biomedical subjects

S T Holgate

Publications and source records attributed to S T Holgate.

At least 343 records · Page 19Linked to original sources
PubMed1994

Inhaled beclomethasone dipropionate downregulates airway lymphocyte activation in atopic asthma.

It is widely known that inhaled corticosteroids are highly efficacious in the prophylactic treatment of asthma, but the mechanism of this action is not known. In this study we have investigated the effect of 6 wk of therapy with inhaled beclomethasone dipropionate (BDP; daily dose 2,000 micrograms for 2 wk and 1,000 micrograms for 4 wk) in a group of symptomatic individuals with asthma on clinical and physiologic indices of disease activity and on T cell numbers and state of activation in peripheral blood and bronchoalveolar lavage (BAL). This course of treatment had a marked effect of improving all indices of disease activity including symptom scores, morning peak expiratory flow (PEF), variation in PEF, and methacholine PC20 (from a geometric mean of 0.62 to 4.6 mg/ml) but did not alter the total numbers of T cells, identified by the CD3 receptor, or the CD4+ and CD8+ subsets when analyzed in peripheral blood or BAL using flow cytometry. However, BDP treatment had a marked effect in reducing the expression of the activation markers CD25 and HLA-DR (p < 0.02) in T cells recovered by BAL in which these markers were upregulated. A small but significant (p < 0.02) downregulation of HLA-DR expression was also observed on peripheral blood T cells. These data add to the view that T cells are upregulated in the airways of individuals with asthma and are susceptible to inhibition by topical corticosteroids.

Administration, Inhalation↗
PubMed1994

The relationship between pneumonia in early childhood and impaired lung function in late adult life.

This study related respiratory illness documented in the first 2 yr of life to the lung function of 618 men and women with a mean age of 70 yr living in Derbyshire, England. Pneumonia before 2 yr of age was associated with a lower mean FEV1, adjusted for age and height. In men, the difference was -0.65L (95% CI: -1.02, -0.29; p = 0.0005). This estimate did not diminish after adjustment for smoking and asthma. In women, the reduction in mean FEV1 associated with pneumonia before 2 yr of age was smaller and nonsignificant. Bronchitis, measles, and whooping cough before 2 yr of age were not associated with diminished adult lung function in either sex. The findings in men support a causal relationship between pneumonia in early childhood and COPD in late adult life.

Age Factors↗
PubMed1994

Airway effects of local challenge with hypertonic saline in exercise-induced asthma.

Hypertonicity of airway lining fluid has been suggested as the stimulus for bronchoconstriction in exercise-induced asthma. We explored the airway effects of delivering a direct hypertonic stimulus to asthmatic airways via a fiberoptic bronchoscope, comparing hypertonic saline challenge by direct instillation with local aerosol delivery. A group of 18 asthmatic subjects responsive to inhaled hypertonic saline with a history of EIA were studied; the first 9 subjects received local challenge with hypertonic saline by direct instillation, and the next 9 subjects were challenged by local aerosol delivery. A control challenge with isotonic saline by either instillation or aerosol was performed at a same bronchoscopy. Local challenge with hypertonic saline by aerosol delivery was found to be more effective in inducing local bronchoconstriction (8 of 9 subjects) than instillation (2 of 6 subjects). Paired BAL fluid samples and bronchial biopsies were obtained in total of 11 and 9 subjects, respectively. Local challenge with hypertonic saline either by instillation or aerosol produced no significant change in histamine, tryptase, or PGD2 levels in BAL fluid or mast cell numbers and degranulation in bronchial biopsies. A significant correlation was observed between histamine levels in BAL fluid and airway responsiveness to inhaled hypertonic saline (rs = -0.59, p < 0.05). Bronchial biopsies showed evidence of extensive epithelial damage; however, this was not related to airway responsiveness to inhaled hypertonic saline.

Adolescent↗
PubMed1994

Circulating adhesion molecules in asthma.

There is increasing evidence that leukocyte-endothelial adhesion molecules are important in inflammatory airway disease because of their involvement in the primary steps of entrapment and migration of leukocytes to the site of inflammation. Recently, circulating forms of these adhesion molecules have been described, although their origin, fate, and function are still unknown. We have used an antigen capture ELISA to measure the concentrations of circulating intercellular adhesion molecule-1 (cICAM-1), E-selectin (cE-selectin), and vascular cell adhesion molecule-1 (cVCAM-1) in the peripheral blood of 13 atopic and 16 non-atopic normal subjects, 29 patients with stable asthma, and inpatients with acute asthma on Day 1 (n = 38), Day 3 (n = 29), and Day 28 (n = 13) of an asthmatic episode. Circulating ICAM-1 and E-selectin levels were significantly raised in acute asthma on all three study days when compared with those observed in stable asthma, atopic normal, or nonatopic normal volunteers with no significant differences among the latter three groups. Circulating VCAM-1 was not significantly increased in any of the groups studied. There were no correlations among the concentrations of these three circulating adhesion molecules. The elevated concentrations of cICAM-1 and cE-selectin in acute asthma may reflect the extensive inflammatory response occurring in the airways during acute exacerbations of the disease with airway obstruction. It is possible that the cytokine and mediator profiles in acute asthma lead to the preferential synthesis and expression of these two circulating adhesion molecules in comparison with cVCAM-1.

Acute Disease↗
PubMed1994

The effect of the orally active platelet-activating factor antagonist WEB 2086 in the treatment of asthma.

Platelet-activating factor (PAF) may be a major mediator of asthma and bronchial hyperreactivity through its many proinflammatory actions. Specific antagonism of PAF might offer an alternative anti-inflammatory treatment to inhaled corticosteroids. To test this, we have studied the effect of an orally active PAF antagonist, WEB 2086, on the inhaled steroid requirements of symptomatic atopic asthmatics in a double-blind randomized placebo-controlled parallel group study. The inhaled corticosteroid dose required for symptomatic control of asthma was established and further steroid reduction was attempted after treatment with WEB 2086 40 mg three times daily for 12 wk. Of 106 patients recruited, 68 entered the treatment phase and 65 completed 6 wk of treatment. The mean daily corticosteroid dose (SE) at study entry was 1,257 (75) micrograms which was reduced by 323 (66) micrograms during the run-in period without loss of symptomatic control. A further 416 (57) micrograms reduction in inhaled corticosteroid dosage was possible during the treatment phase but this was almost identical in the WEB 2086 and placebo-treated groups, amounting to 353 (92) and 481 (65) micrograms/day respectively (not significant [NS]). Rate of relapse following corticosteroid reduction was a continuous variable and relapse occurred at different times depending on the variable used to define it. Time to relapse measured by an increase in symptoms correlated with disease duration (r = 0.41, p < 0.01) and with the dose of inhaled corticosteroid at study entry (r = 0.36, p < 0.01) but no other measured variable predicted the time to relapse.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1994

Episodes of respiratory morbidity in children with cough and wheeze.

An important feature of "asthma" in children is the occurrence of repeated episodes of airflow obstruction lasting days or weeks. In this 1-yr longitudinal study, we investigated the nature of these episodes and their relationship to other indices of asthma. A random sample of children aged 7 and 8 yr reporting either cough or wheeze was invited to attend for skin testing. Ninety-six atopic children, half with cough and half with wheeze, and 96 nonatopic children, again half with cough and half with wheeze, were selected to join a longitudinal study. All children recorded twice daily peak expiratory flow (PEF) measurements and a daily 10-point symptom score. One hundred eighty-three children (95.3%) successfully completed the study. Episodes of respiratory morbidity, defined as falls in PEF to less than 1.5 standard deviations (SD) below subject mean lasting for more than 2 days, were identified and the 642 resulting episodes examined. Episodes were more common in autumn and winter (p = 0.003 to 0.017). The mean number of episodes per child was 3.5 (range 0 to 8): 94 (51.4%) children experienced more than three episodes, 54 (30.0%) experiencing five or more. The average duration of episodes was 4.1 days (range 2 to 27 days), with 44 (24%) subjects demonstrating episodes of average duration of 5 days or more and 18 (10%) of greater than 7 days. Episodes were more severe in children with wheeze (p = 0.013) and slightly more frequent in those with cough alone (p < 0.05). Atopy had no effect on episode frequency, duration, or magnitude.

Asthma↗
PubMed1994

Influence of interleukin-8 challenge in the nasal mucosa in atopic and nonatopic subjects.

Interleukin-8 (IL-8) is a major cytokine in the recruitment of neutrophils (polymorphonuclear leukocytes) to areas of inflammation. It also activates T lymphocytes and cytokine-primed basophils and eosinophils and therefore may be implicated as an effector in allergic inflammation. IL-8 has also been identified as a mediator in such inflammatory pulmonary conditions as cystic fibrosis, allergen challenge, and sarcoidosis. To investigate the bioactivity of IL-8 in humans, we examined the effects of nasal challenge with human recombinant IL-8 in a double-blind placebo-controlled crossover study in which nasal resistance and rhinitic symptoms were monitored for 4 h after challenge. Cellular infiltration was quantified on differentially stained nasal smears obtained at hourly intervals. Cellular responses caused by in vivo priming were assessed by a comparison of atopic and nonatopic patient groups. A significant neutrophilic infiltrate in smear samples was observed in all patients challenged with IL-8 from 12 +/- 4% (mean +/- SEM) at baseline to 60 +/- 6% after 4 h; placebo challenge resulted in an increase in neutrophils to 30 +/- 4% (p < 0.04). Additionally, a significant increase in cumulative eosinophil recruitment occurred over the challenge period. Nasal resistance was significantly increased 10 min after instillation of IL-8 in all subjects compared with placebo, but there was no difference between atopic and nonatopic subjects. Nasal rhinitic symptoms were also increased in all subjects receiving IL-8 compared with placebo. In a further study in 19 subjects, nasal biopsy was performed 3 h after IL-8 or placebo challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Immunohistochemical analysis of nasal biopsies during rhinovirus experimental colds.

Human rhinoviruses (HRV) are an important cause of upper respiratory tract infection and are etiologically linked with asthma exacerbations. However, the mechanisms of virus-induced inflammation are largely unknown. We examined nasal mucosal biopsies for the presence of an associated inflammatory cellular infiltrate during experimental rhinovirus infection. A group of 21 adult volunteers (10 atopic) had baseline nasal biopsies, followed 2 wk later by inoculation with HRV Serotype 16. Nasal biopsies were taken on Day 4 of the cold and again 6-10 wk later. Infection was documented by symptom scores, viral culture, and seroconversion. The biopsies were fixed in acetone and processed into glycol methacrylate resin for semithin sectioning. Mast cells, eosinophils, lymphocytes, and neutrophils were identified with appropriate monoclonal antibodies and a streptavidin-biotin horseradish peroxidase technique. There were no significant changes in the numbers of inflammatory cells present during the cold or the convalescent period compared with baseline biopsies (Wilcoxon paired, p > 0.05). There were also no differences between normal and atopic groups. We suggest that rhinoviral colds are not associated with increased inflammatory cellularity and that other mechanisms, such as increased mediator release, are responsible for coryzal symptoms.

Adolescent↗
PubMed1994

Detection of rhinovirus infection of the nasal mucosa by oligonucleotide in situ hybridization.

Human rhinoviruses (HRVs) cause the common cold and often induce lower airway symptoms such as cough and wheezing. Although HRV infection is presumed to involve primarily ciliated epithelial cells, this has not been confirmed in vivo, and the cellular distribution and spread of infection as well as the pathogenesis of cold related nasal and chest symptoms remain speculative. We have developed in situ hybridization (ISH) to explore localization of the virus to airway tissues, employing HRV 16-derived oligonucleotide probes after sequencing part of the genome of this serotype. A reverse transcription-polymerase chain reaction was used to generate DNA from HRV 16 for sequencing; this yielded 305 nucleotide bases that showed considerable homology to other HRVs. The HRV 16 sequence was used to design oligonucleotides functioning as antisense and sense probes. These probes as well as random sequence and pathogen control oligonucleotides were applied to HRV-infected cell-clot complexes and finally to sections from six paired nasal biopsies obtained before, during, or after HRV-proven colds. Specificity of hybrids was established by the absence of signal in uninfected tissue, in cells infected with other viruses, after RNase pretreatment, and with application of control probes. Hybridization signals were observed in epithelial cells in three of six biopsies obtained during a cold, using probes to viral (+) strand; intermediate (-) strand, implying viral replication, was present in one biopsy. Evidence for infection of nonepithelial cells was inconclusive. HRVs cause productive infection of nasal epithelium during a cold and their intracellular localization may produce perturbation of inflammatory mediators and cytokine profiles.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1994

Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines.

Asthma is characterized by the presence of an inflammatory cell infiltrate in the bronchial mucosa consisting of activated mast cells, eosinophils, and T cells. Several cytokines are considered to play a pivotal role in this response, particularly interleukin (IL)-4, IL-5, IL-6, and tumor necrosis factor-alpha (TNF-alpha). In this study, we have used immunohistochemistry applied to thin glycol methacrylate sections of bronchial mucosal biopsies to define the cellular provenance of these cytokines in normal and asthmatic airways. Both the asthmatic and normal mucosa contained numerous cells staining positively for all four cytokines, with the majority identified as mast cells by their tryptase content. Eosinophils also accounted for some IL-5 immunostaining in the asthmatic biopsies. By using two monoclonal antibodies directed to different epitopes of IL-4, we provide tentative evidence for enhanced IL-4 secretion in asthma. Similarly, a sevenfold increase in the number of mast cells staining for TNF-alpha in the asthmatic biopsies suggests that this cytokine is also up-regulated in this disease. These findings clearly identify human mast cells as a source of IL-4, IL-5, IL-6, and TNF-alpha and add to the view that, along with T cells, mast cells may play an important role in initiating and maintaining the inflammatory response in asthma.

Adult↗
PubMed1994

Bronchial biopsy evidence for leukocyte infiltration and upregulation of leukocyte-endothelial cell adhesion molecules 6 hours after local allergen challenge of sensitized asthmatic airways.

We have examined the mucosal changes occurring in bronchial biopsies from six atopic asthmatics 5-6 h after local endobronchial allergen challenge and compared them with biopsies from saline-challenged segments from the same subjects at the same time point. All the subjects developed localized bronchoconstriction in the allergen-challenged segment and had a decrease in forced expiratory volume in 1 s (FEV1) (P < 0.01) and a decrease in their methacholine provocative concentration of agonist required to reduce FEV1 from baseline by 20% (P < 0.05) 24 h postchallenge. At 6 h we observed an increase in neutrophils (P = 0.03), eosinophils (P = 0.025), mast cells (P = 0.03), and CD3+ lymphocytes (P = 0.025), but not in CD4+ or CD8+ lymphocyte counts. We also detected an increase in endothelial intercellular adhesion molecule type 1 (P < 0.05) and E-selectin (P < 0.005), but not vascular cell adhesion molecule type 1 expression with a correlative increase in submucosal and epithelial LFA+ leucocytes (P < 0.01). Thus, in sensitized asthmatics, local endobronchial allergen instillation leads to an increased inflammatory cell infiltrate of the airway mucosa that involves upregulation of specific adhesion molecules expressed on the microvasculature.

Adult↗
PubMed1994

Effect of inhaled bradykinin on indices of airway responsiveness in asthmatic subjects.

Asthma is characterized by airway hyperresponsiveness, a physiopathological abnormality which may result from the complex interplay between inflammatory cells and proinflammatory mediators. Although kinins are thought to play a role in the pathogenesis of bronchial asthma, it is not known whether bradykinin is able to induce airway hyperresponsiveness. We have, therefore, investigated the effect of inhaled bradykinin on the changes in airway calibre and in airway hyperresponsiveness to histamine, in a double-blind, randomized study of nine asthmatic subjects. Subjects were studied on two study periods, separated by at least 15 days. On the first day of each study period, subjects inhaled either a single dose of bradykinin or methacholine (placebo) with changes in airway calibre being followed as forced expiratory volume in one second (FEV1) and as the maximum expiratory flow rate measured at 70% of the vital capacity below total lung capacity (TLC) from a partial forced expiratory manoeuvre (Vp30) at 3, 5, 10, 15, 30, 45 and 60 min, and then every hour for 7 h. Airway responsiveness to histamine, expressed as the provocative concentrations producing a 20% fall in FEV1 and 40% fall in Vp30 (PC20FEV1 and PC40Vp30), was measured at 3 and 7 h after inhaling the agonists, then on days 1, 3, 7 and 14. Inhalation of bradykinin caused rapid bronchoconstriction that peaked at 3-5 min. When compared to placebo, no significant difference in histamine responsiveness was seen after bradykinin in terms of changes in PC20FEV1 values.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1994

Terbutaline via pressurised metered dose inhaled (P-MDI) and Turbuhaler in highly reactive asthmatic patients.

There is some concern over the environmental consequences of chlorofluorocarbons (CFCs) used in pressurized metered-dose inhalers (p-MDIs). Turbuhaler was designed to deliver a drug as a dry powder without administering additives directly to the airways. The aim of this study was to evaluate the comparative irritant and bronchodilating effects of the same dose of terbutaline delivered by a p-MDI and via Turbuhaler. Ten symptomatic, asthmatic patients, with highly reactive airways (provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20) < 0.2 mg.ml-1), inhaled, on separate days, 0.25 mg terbutaline via p-MDI or Turbuhaler. Changes in airway calibre were followed as specific airways conductance (sGaw). On a third day, patients inhaled from a placebo p-MDI containing all constituents except terbutaline. The study was conducted in a single-blind fashion and in random order. There were no significant differences in baseline sGaw on any of the study days. Inhalation of terbutaline from the p-MDI produced a transient percentage fall in sGaw at 1 min, reaching a mean maximum +/- SD of 17 +/- 8% at 10 s and then returning to baseline value after 20 s, followed by a progressive increase in sGaw to a maximum of 39 +/- 45% above baseline at 45 min. In contrast, inhalation of terbutaline via Turbuhaler caused no significant bronchoconstriction (fall in sGaw, 3 +/- 16%) at 10 s and achieved a greater increase in sGaw, reaching 63 +/- 51% at 45 min, although just failing to reach statistical significance compared to terbutaline p-MDI inhalation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

A new method of quantification of the pulmonary regional distribution of aerosols using combined CT and SPECT and its application to nedocromil sodium administered by metered dose inhaler.

Aerosols of nedocromil sodium labelled with 99Tcm were delivered on 20 separate occasions to healthy male volunteers. Planar and single photon emission computerized tomography (SPECT) gamma scintigraphy were immediately performed to assess the pulmonary regional distribution of delivered aerosol. On a separate occasion volunteers were imaged using X-ray computed tomography (CT). Alignment of SPECT and CT images was performed using marked anatomical features and the anterior and lateral skin outlines. CT images provided data for attenuation correction and were used to define the anatomical lung volume. Central to peripheral (CP) ratios of deposited activity were calculated from volumes of interest in coronal and transverse sections of the right lung. These were compared with CP ratios obtained from planar images obtained immediately following aerosol inhalation. Volumetric CP ratio correlated significantly with immediate planar CP ratio (p < 0.001). Analysis of deposition in the whole right lung was performed by separating the SPECT lung data into a series of thin concentric shells centred on the entry of the right main bronchus. Measures were defined for describing the variation of deposition density and cumulative total deposition with distance from the lung centre. These showed significant correlation with planar CP ratio (p < 0.001). SPECT analysis using CT is consistent with planar measures of aerosol deposition but offers a more complete quantification of aerosol penetration and absolute deposited activity within the whole lung. It is a valuable new tool for aerosol analysis.

Administration, Inhalation↗
PubMed1993

Dexamethasone treatment fails to reduce oxygen-induced lung injury in the preterm guinea pig. Effects on pulmonary inflammation and antioxidant status.

Dexamethasone (10 mg/kg/day) or vehicle was administered in a randomized, controlled fashion to 3-day preterm guinea pigs exposed to either 21% oxygen or 95% oxygen for 72 hr and maintained in room air for a further 96 hr. Treatment with dexamethasone had no effect on survival of preterm pups maintained in either 21% or 95% O2. Dexamethasone treatment reduced the growth rate of pups, the effect occurring earlier (0-3 days) in 21% O2-treated pups than in 95% O2-treated pups (5-7 days). Exposure to 95% O2 reduced the survival rate of preterm animals (73% vs 100%, P < 0.05). Surviving pups developed acute lung injury, characterized by the accumulation of a protein-rich exudate in the alveoli and an infiltration of inflammatory cells, particularly neutrophils into the lung. Dexamethasone treatment attenuated the pulmonary inflammatory cell infiltration, in particular neutrophils, both during oxygen exposure (16.4 x 10(4) vs 9.4 x 10(4)/mL; P < 0.05) and following return to ambient conditions (28.0 x 10(4) vs 5.1 x 10(4)/mL; P < 0.05). Elastase activity in bronchoalveolar lavage fluid, which was primarily of neutrophil origin, was unchanged by dexamethasone treatment. Dexamethasone-treated pups had increased pulmonary antioxidant enzyme activities (Cu/Zn-superoxide dismutase; Mn-superoxide dismutase, catalase and glutathione peroxidase) during recovery from oxidative injury. Although there was both a marked reduction in numbers of neutrophils in the lung and elevated pulmonary antioxidant enzyme activities in dexamethasone-treated pups, the degree of microvascular permeability, as determined by both the lung wet weight/dry weight ratio and the presence of plasma proteins in the lavage fluid, was unchanged. Combined, these results imply that dexamethasone, although capable of blunting the influx of neutrophils to the hyperoxia-exposed lung and inducing antioxidant defences in the immature lung, cannot modify the progression of acute oxygen-induced injury of the immature lung.

Amino Acid Sequence↗
PubMed1993

Immunolocalization of cytokines in the nasal mucosa of normal and perennial rhinitic subjects. The mast cell as a source of IL-4, IL-5, and IL-6 in human allergic mucosal inflammation.

Allergic mucosal inflammation is characterized by the presence of cell infiltration, predominantly with IgE-sensitized mast cells and activated eosinophils, and appears to be regulated by the local production and release of several cytokines, particularly IL-4 and IL-5. Although attention has focused on the Th2 subpopulation of CD4+ T lymphocytes as an important source of these cytokines, human mast cells have been shown to both store and secrete IL-4 and TNF-alpha. To investigate the expression of cytokines relevant to allergic inflammation and to identify their cellular localization within the nasal mucosa, we have undertaken specific immunohistochemical staining of thin sections of inferior turbinate biopsies from patients with perennial allergic rhinitis and, for comparison, from nonatopic healthy volunteers. The cytokines investigated were IL-4, IL-5, IL-6, and IL-8. In both the normal and rhinitic biopsies numerous cells immunoreactive for IL-4, IL-5, and IL-6 were seen. Staining of adjacent 2-microns sections for CD3, mast cell tryptase, and eosinophil cationic protein revealed that 90% of the IL-4 immunoreactive cells were mast cells, with biopsies from rhinitic subjects containing significantly more IL-4+ cells than biopsies from normal controls (p = 0.02), especially when assessed with the anti-IL-4 mAb 3H4. Mast cells also accounted for > 90% of IL-6 and > 50% of IL-5 immunoreactive cells. IL-5 immunoreactivity was also localized to eosinophils, whereas IL-8 localized predominantly to the nasal epithelium in both groups. No cytokines were found in association with T lymphocytes. These findings indicate that the mast cell is an important source of preformed cytokines and as such may contribute to the chronicity of the mucosal inflammation that characterizes allergic rhinitis.

Adult↗