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Biomedical subjects

S T Holgate

Publications and source records attributed to S T Holgate.

At least 73 records · Page 4Linked to original sources
PubMed2002

The inflammatory marker serum eosinophil cationic protein (ECP) compared with PEF as a tool to decide inhaled corticosteroid dose in asthmatic patients.

The objective of this study was to compare the inflammatory marker eosinophil cationic protein (ECP) with peak expiratory flow (PEF) in determining the therapeutic needs of inhaled corticosteroids in asthma patients assessed as asthma symptoms. A randomized, single-blind study over 6 months was performed at six specialist centres in Europe. In total, 164 adult patients with moderate to severe symptomatic asthma and regular use of inhaled corticosteroids were included. After a run-in period of 2 weeks patients were randomly allocated to the ECP or the PEF monitoring group. The dose of inhaled cort costeroids was adjusted every fourth week based on the current serum ECP value or pre-bronchodilator morning PEF values as surrogate markers of therapeutic needs. At the end of the study there were no statistically significant differences in the mean daily symptom score or the percentage of symptom-free days between the two groups. The mean daily dose of inhaled corticosteroids was similar in the two groups at the start of the study but the algorithms used to adjust the dose of inhaled corticosteroids resulted in an increased use of inhaled corticosteroids in both groups. The mean daily dose of inhaled corticosteroids over the whole study period was significantly lower in the ECP group compared withthe PEF group (1246 vs. 1667 microg, P = 0.026). In the ECP group, forced expiratory volume in I sec (FEV)% predicted was lower at the end ofthe study compared with the begining (92% vs. 87%, P = 0 .0009), although there was no significant difference between the two groups. None of the used algorithms for ECP and PEF led to improvement in symptom scores, in spite of increased doses of inhaled corticosteroids. In this respect, both methods were equivalent and insufficient. Recommendations suggesting lung function tests in current guidelines may be difficult to translate into clinical practice, however, a combination of inflammatory markers, lung function and symptoms may still improve asthma control.

Administration, Inhalation↗
PubMed2002

Role of cysteinyl leukotrienes in adenosine 5'-monophosphate induced bronchoconstriction in asthma.

BACKGROUND: Adenosine induced bronchoconstriction in patients with asthma is thought to be mediated by the synthesis and release of autacoids from airway mast cells. In vitro, adenosine induced constriction of asthmatic bronchi is blocked by a combination of specific histamine and cysteinyl leukotriene receptor antagonists, but the relative contribution of these mediators in vivo is unclear. We hypothesised that adenosine induced bronchoconstriction in asthmatic patients may be blocked by pretreatment with the orally active selective cysteinyl leukotriene-1 (CysLT(1)) receptor antagonist, montelukast. METHODS: In a randomised, double blind, crossover study, oral montelukast (10 mg) or placebo was administered once daily on two consecutive days to 18 patients with mild to moderate persistent atopic asthma. Incremental doses of adenosine 5'-monophosphate (AMP) from 0.39 to 400 mg/ml were inhaled by dosimeter and the dose producing a 20% fall in FEV(1) (PC(20)AMP) after AMP inhalation was recorded. Leukotriene E(4) (LTE(4)) urinary concentrations were measured by enzyme immunoassay 4 hours after AMP challenge. RESULTS: Montelukast pretreatment provided highly significant protection against adenosine induced bronchoconstriction, with geometric mean PC(20)AMP values of 52.6 mg/ml (95% CI 35.2 to 78.7) after placebo and 123.9 mg/ml (95% CI 83.0 to 185.0) after montelukast (p=0.006). The geometric mean of the montelukast/placebo PC(20)AMP ratio was 2.4 (95% CI 1.3 to 4.2). Montelukast had no significant effect on 4 hour urinary excretion of LTE(4) compared with placebo. CONCLUSIONS: Selective CysLT(1) receptor antagonism with montelukast provides highly significant protection against AMP induced bronchoconstriction in patients with atopic asthma, implying that cysteinyl leukotrienes are generated from airway mast cells through preferential activation of their A(2B) receptors.

Acetates↗
PubMed2002

A defective type 1 response to rhinovirus in atopic asthma.

BACKGROUND: Rhinoviruses (RVs) are the most frequent precipitants of the common cold and asthma exacerbations, but little is known about the immune response to these viruses and its potential implications in the pathogenesis of asthma. METHODS: Peripheral blood mononuclear cells (PBMC) from patients with atopic asthma and normal subjects were exposed to live or inactivated RV preparations. Levels of interferon (IFN)gamma and interleukins IL-12, IL-10, IL-4, IL-5 and IL-13 were evaluated in the culture supernatants with specific immunoassays. RESULTS: Exposure of PBMC to RVs induced the production of IFNgamma, IL-12, IL-10, and IL-13. Cells from asthmatic subjects produced significantly lower levels of IFNgamma and IL-12 and higher levels of IL-10 than normal subjects. IL-4 was induced only in the asthmatic group, while the IFNgamma/IL-4 ratio was more than three times lower in the asthmatic group. CONCLUSIONS: This evidence suggests that the immune response to RVs is not uniquely of a type 1 phenotype, as previously suggested. The type 1 response is defective in atopic asthmatic individuals, with a shift towards a type 2 phenotype in a way similar, but not identical, to their aberrant response to allergens. A defective type 1 immune response to RVs may be implicated in the pathogenesis of virus induced exacerbations of asthma.

Adult↗
PubMed2002

Evolving concepts on the value of adenosine hyperresponsiveness in asthma and chronic obstructive pulmonary disease.

Adenosine is a purine nucleoside which mediates a variety of cellular responses relevant to asthma and COPD through interaction with specific receptors. Administration of adenosine by inhalation to patients with asthma and COPD is known to cause concentration related bronchoconstriction. Responses elicited by this purine derivative in asthma and COPD should not be considered as a mere reflection of non-specific airways hyperresponsiveness. Evaluation of airways responsiveness by adenosine induced bronchoconstriction may be valuable in differentiating asthma from COPD, monitoring of anti-inflammatory treatment in asthma, surveying disease progression, and assessing disease activity in relation to allergic airways inflammation.

Adenosine↗
PubMed2002

Variability and lack of predictive ability of asthma end-points in clinical trials.

While a consensus definition of the clinical parameters important in asthma control exists, an adequate objective definition of a response to asthma treatment and parameters for prediction of that response remain undefined. Given that asthma is a complex biological disease and that different parameters may measure dissimilar aspects of the disease status, this study assessed the relationship among several end-points of asthma control, and attempted to select a combination of variables measured before (baseline characteristics) or early in asthma therapy which would be predictive of a long-term clinical response. Data from two previously reported clinical studies which included montelukast, inhaled beclomethasone, and placebo in mild-to-moderate asthmatics (n=1,576) were analysed. The forced expiratory volume in one second (FEV1), daily symptoms score (DSS), beta-agonist use, and morning peak expiratory flow (PEFAM) were recorded during the baseline period and throughout the 12-week treatment period. For the long-term response, as measured during the last 9 weeks of treatment, there was a large within-patient variability and no more than a moderate correlation between the changes in FEV1 and PEFAM; DSS and FEV1; and DSS and beta-agonist use. The overall predictive values for FEV1 and DSS were 70-80%. The results showed that multiple measurements over a length of time are needed to establish a more complete profile of response, and that demographic and early treatment responses had a small but inadequate ability to predict future response. This study demonstrates the complex relationship among asthma end-points and the difficulty of reliably estimating long-term response using common, surrogate clinical markers of asthma control.

Adolescent↗
PubMed2001

Leukotriene and prostanoid pathway enzymes in bronchial biopsies of seasonal allergic asthmatics.

Cysteinyl-leukotrienes and prostaglandin D2 generated by the 5-lipoxygenase (5-LO) and cyclooxygenase (COX) pathways, respectively, cause bronchoconstriction, leukocyte recruitment, and bronchial hyperresponsiveness in asthma. We characterized the cellular expression of 5-LO and COX enzymes using immunohistochemistry on bronchial biopsies from 12 allergic asthmatic patients before and during seasonal exposure to birch pollen. Bronchial responsiveness (p = 0.004) and symptoms (p < 0.005) increased and peak expiratory flow (PEF; p < or = 0.02) decreased in the pollen season. In-season biopsies had 2-fold more cells immunostaining for 5-LO (p = 0.02), 5-LO-activating protein (FLAP; p = 0.04), and leukotriene (LT)A4 hydrolase (p = 0.05), and 4-fold more for the terminal enzyme for cysteinyl-leukotriene synthesis, LTC4 synthase (p = 0.02). Immunostaining for COX-1, COX-2, and PGD2 synthase was unchanged. Increased staining for LTC4 synthase was due to increased eosinophils (p = 0.035) and an increased proportion of eosinophils expressing the enzyme (p = 0.047). Macrophages also increased (p = 0.019), but mast cells and T-lymphocyte subsets were unchanged. Inverse correlations between PEF and 5-LO(+) cell counts link increased expression of 5-LO pathway enzymes in eosinophils and macrophages within the bronchial mucosa to deterioration of lung function during seasonal allergen exposure.

Adult↗
PubMed2001

Effects of budesonide and formoterol on NF-kappaB, adhesion molecules, and cytokines in asthma.

The asthmatic inflammatory response can be attenuated by corticosteroids and in part by beta(2)-agonists. We investigated if these effects are accompanied by a downregulation in nuclear factor kappa B (NF-kappaB), a transcription factor regulating many of the cytokine and adhesion molecule genes expressed in allergic inflammation. Bronchial biopsies were taken before and after 8 wk treatment with formoterol, budesonide, or placebo from atopic asthmatics. Biopsies were processed into glycol methacrylate and stained immunohistochemically for eosinophils (as an index of inflammation), activated and total NF-kappaB, adhesion molecules, and cytokines. After budesonide treatment there was a significant decrease in the number of submucosal cells staining for total NF-kappaB, granulocyte macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha), accompanied by a significant decrease in mucosal eosinophils and expression of vascular cell adhesion molecule-1 (VCAM-1) in the endothelium and interleukin-8 (IL-8) in the epithelium. After formoterol treatment there was a significant decrease in eosinophils and the epithelial expression of activated NF-kappaB, but these changes were not accompanied by reduced immunoreactivity for adhesion molecules or cytokines. We conclude that at least some of the therapeutic efficacy of inhaled corticosteroids is mediated through inhibition of NF-kappaB-regulated gene expression, whereas the reduction in airway eosinophilia by long-acting beta(2)-agonists probably operates through alternative pathways.

Administration, Topical↗
PubMed2001

Is electrodermal testing as effective as skin prick tests for diagnosing allergies? A double blind, randomised block design study.

OBJECTIVE: To evaluate whether electrodermal testing for environmental allergies can distinguish between volunteers who had previously reacted positively on skin prick tests for allergy to house dust mite or cat dander and volunteers who had reacted negatively to both allergens. DESIGN: Double blind, randomised block design. SETTING: A general practice in southern England. PARTICIPANTS: 15 volunteers who had a positive result and 15 volunteers who had a negative result on a previous skin prick test for allergy to house dust mite or cat dander. INTERVENTION: Each participant was tested with 6 items by each of 3 operators of the Vegatest electrodermal testing device in 3 separate sessions (a total of 54 tests per participant). For each participant the 54 items comprised 18 samples each of house dust mite, cat dander, and distilled water, though these were randomly allocated among the operators in each session. A research nurse sat with the participant and operator in all sessions to ensure blinding and adherence to the protocol and to record the outcome of each test. OUTCOME: The presence or absence of an allergy according to the standard protocol for electrodermal testing. RESULTS: All the non-atopic participants completed all 3 testing sessions (810 individual tests); 774 (95.5%) of the individual tests conducted on the atopic participants complied with the testing protocol. The results of the electrodermal tests did not correlate with those of the skin prick tests. Electrodermal testing could not distinguish between atopic and non-atopic participants. No operator of the Vegatest device was better than any other, and no single participant's atopic status was consistently correctly diagnosed. CONCLUSION: Electrodermal testing cannot be used to diagnose environmental allergies.

Adult↗
PubMed2001

Pharmacokinetics of andolast after administration of single escalating doses by inhalation in mild asthmatic patients.

The pharmacokinetics of andolast, a new tetrazolyl-benzamido derivative with antiallergic, antiinflammatory, mucosal protective and antisecretive activities, have been investigated in patients suffering from mild asthma (FEV(1) > or =70% of predicted) in whom obstruction was reversible (FEV(1) increase > or =15% of initial) after the administration of 0.2 mg of salbutamol by inhalation. Twelve out-patients (seven males and five females) were enrolled in the present study and were treated with a single dose of andolast of 2, 4 and 8 mg by inhalation using the MIAT Monohaler device according to a randomised crossover design. Plasma samples were collected before drug administration and up to 540 min after dosing. Andolast plasma concentrations were determined using a validated LC-MS/MS method with a limit of quantitation of 0.2 ng ml(-1). Pharmacokinetic analysis was carried out using standard non-compartmental methods. In addition, andolast safety and tolerability were evaluated by performing standard laboratory tests, by recording vital signs and ECGs and by monitoring the occurrence of adverse events throughout the study period. Andolast was absorbed after inhalation and was available to the systemic circulation. The mean peak plasma concentrations were 6.3, 10.9 and 30.5 ng ml(-1) at the three doses, respectively, and occurred at 30, 52.5 and 30 min (median t(max)). The mean AUC(t) values were 1852, 2889 and 7677 ng min ml(-1). The apparent plasma clearance (CL/F) and volume of distribution (V(z)/F) were, respectively, 1168 ml min(-1) and 430 l at the dose of 2 mg, 1143 ml min(-1) and 468 l at the dose of 4 mg, and 1141 ml min(-1) and 486 l at the dose of 8 mg. The apparent elimination half-life averaged 4.5, 5.0 and 4.6 h at the three doses, respectively. Even though the small number of subjects participating in the present study reduced the power of the statistical test, there was no statistically significant evidence of non-proportionality for all the andolast pharmacokinetic parameters calculated at the three doses. Thus, the data obtained as a whole suggest that andolast pharmacokinetics are dose-independent in the dose range investigated. Finally, the safety and tolerabilty of the drug administered to mild asthmatic patients was good up to the maximum investigated dose of 8 mg.

Administration, Inhalation↗
PubMed2001

Basement membrane pores in human bronchial epithelium: a conduit for infiltrating cells?

This study reports the presence of oval-shaped pores in the basement membrane of the human bronchial airway that may be used as conduits for immune cells to traffic between the epithelial and mesenchymal compartments. Human bronchial mucosa collected after surgery was stripped of epithelial cells without damaging the basement membrane. Both scanning and transmission electron microscopy showed oval-shaped pores 0.75 to 3.85 microm in diameter in the bronchial basement membrane at a density of 863 pores/mm2. Transmission electron microscopy showed that the pores spanned the full depth of the basement membrane, with a concentration of collagen-like fibers at the lateral edges of the pore. Infiltrating cells apparently moved through the pores, both in the presence and absence of the epithelium. Taken together, these results suggest that immune cells use basement membrane pores as predefined routes to move between the epithelial and mesenchymal compartments without disruption of the basement membrane. As a persistent feature of the basement membrane, pores could facilitate inflammatory cell access to the epithelium and greatly increase the frequency of intercellular contact between trafficking cells.

Basement Membrane↗
PubMed2001

Linkage analysis of the 5q31-33 candidate region for asthma in 240 UK families.

Atopy and asthma are complex genetic diseases resulting from the interactions of a number of genetic and environmental factors. We had previously reported allelic association between the IL9 marker on chromosome 5q31-33 and atopy. In order to further investigate the role of susceptibility genes on 5q31-33 in the development of atopy and asthma we have studied 240 UK families comprising 131 families selected at random, 60 multiplex families with affected sib pairs, and 49 single proband nuclear families. Polymorphic markers on 5q31-33 were genotyped and both single and multipoint linkage analysis was undertaken using the BETA program. We have used both affection status and quantitative scores for atopy and asthma for phenotypic variables, combining data into scores for asthma and atopy. The strongest suggestion of linkage using multipoint analysis was centred around D5S410 with a maximum Lod of 1.946 at location 171.3 cM and a standard error of 3.3 for the asthma quantitative score. There was no evidence of linkage with atopy, the atopy quantitative score or total serum IgE.

Asthma↗
PubMed2001

Rhinovirus infection up-regulates eotaxin and eotaxin-2 expression in bronchial epithelial cells.

BACKGROUND: Human rhinoviruses (RVs) are the most common precipitants of asthma exacerbations. RV infection of bronchial epithelium results in local airway inflammation inducing eosinophil recruitment and activation. Induction of eosinophil chemoattractants could represent a central mechanism, as well as a prime target for intervention. OBJECTIVE: To assess the effect of RV infection on mRNA expression and production of eosinophil chemoattractants by bronchial epithelial cells in-vitro. METHODS: BEAS-2B cells were infected with major and minor RVs and the mRNA expression of IL-8, RANTES, MIP-1alpha, eotaxin, eotaxin-2, MCP-2, MCP-3 and MCP-4 was assessed by reverse transcription PCR. In cases where mRNA induction was observed, a fluoroimmunoassay was used to confirm protein production. To assess the virus-specificity of the observed reactions, cells were also exposed to inactivated RVs. RESULTS: RV infection was able to up-regulate mRNA expression of IL-8, RANTES, MIP-1alpha, eotaxin and eotaxin-2, did not affect MCP-4, while MCP-2 and MCP-3 were not expressed either at baseline or after virus infection. Protein production was confirmed for IL-8, RANTES and eotaxin, but not for MIP-1alpha. When RVs were inactivated cytokine up-regulation was almost completely lost. CONCLUSION: Infection of bronchial epithelial cells with RVs results in the production of a wide array of mediators that are able to chemoattract eosinophils. These include the eosinophil-specific molecules eotaxin and eotaxin-2, in addition to IL-8 and RANTES, which are the most abundant. Eosinophil recruitment after RV infection of bronchial epithelium could represent a central event in the pathogenesis of virus-induced asthma exacerbations.

Bronchi↗
PubMed2001

Basic fibroblast growth factor in asthma: measurement in bronchoalveolar lavage fluid basally and following allergen challenge.

Airway remodeling in asthma refers to a collection of chronic structural changes including subepithelial fibrosis, airway smooth muscle hypertrophy/hyperplasia, and possibly angiogenesis. The mechanisms leading to remodeling are not well defined. One molecule of possible relevance is basic fibroblast growth factor (bFGF), which is a potent mitogen for fibro-blasts, airway smooth muscle cells, and endothelial cells. To test the hypothesis that bFGF expression is increased in asthma, we measured levels of the growth factor in bronchoalveolar lavage (BAL) fluid. Basally, BAL fluid bFGF concentrations were significantly higher in subjects with atopic asthma than in control subjects without asthma (median 0.22 vs 0.06 pg/mL, P = .003). The effect of acute allergen exposure was examined with a segmental bronchoprovocation model in a separate group of subjects with atopic asthma. Ten minutes after segmental bronchoprovocation there was a 5-fold increase in bFGF levels in BAL fluid recovered from allergen-challenged sites compared with control saline-challenged sites (1.52 vs 0.30 pg/mL, P < .002). We conclude that basal levels of BAL fluid bFGF are increased in atopic asthma and that a further increase occurs in response to acute allergen exposure. These findings lend support to the hypothesis that bFGF is implicated in airway remodeling in asthma.

Adult↗
PubMed2001

Expression of the high-affinity IgE receptor on peripheral blood dendritic cells: differential binding of IgE in atopic asthma.

BACKGROUND: Dendritic cells can express the high-affinity IgE receptor (FcepsilonRI), which, in the presence of specific IgE, facilitates the uptake of allergen, leading to increased activation of allergen-specific T cells. FcepsilonRI expression by dendritic cells is higher in the airways of atopic asthmatic subjects than in those of healthy, nonatopic control subjects. OBJECTIVE: The aims of this study were to determine whether a similar difference in FcepsilonRI expression occurs between dendritic cells in the peripheral blood of atopic asthmatic subjects and healthy individuals and also whether an altered ability of FcepsilonRI(+) peripheral blood dendritic cells to bind IgE accompanies the atopic asthmatic state. METHODS: Flow cytometry was used to analyze the surface expression of FcepsilonRI and exogenously bound IgE on dendritic cells identified as lineage negative (CD3, CD14, CD16, CD19, and CD56) and HLA-DR bright. RESULTS: The total expression of FcepsilonRI on the surface of dendritic cells from healthy and asthmatic subjects was not significantly different. However, in vivo, dendritic cells from atopic asthmatic subjects had higher levels of receptor occupancy by IgE and bound exogenous IgE in vitro more efficiently than dendritic cells from healthy subjects. CONCLUSION: The similar levels of expression of FcepsilonRI on peripheral blood dendritic cells from healthy and asthmatic subjects suggest that the local environment in the airway is responsible for the upregulation of surface FcepsilonRI on airway dendritic cells in asthma. The results also suggest that the functional ability of FcepsilonRI to bind IgE is differentially controlled in the atopic state.

Adolescent↗