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Stephen T Holgate

Publications and source records attributed to Stephen T Holgate.

At least 55 records · Page 3Linked to original sources
PubMed2004

Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma.

IgE plays an important role in allergic asthma. We hypothesized that reducing IgE in the airway mucosa would reduce airway inflammation. Forty-five patients with mild to moderate persistent asthma with sputum eosinophilia of 2% or more were treated with humanized monoclonal antibody against IgE (omalizumab) (n = 22) or placebo (n = 23) for 16 weeks. Outcomes included inflammatory cells in induced sputum and bronchial biopsies, and methacholine responsiveness. Treatment with omalizumab resulted in marked reduction of serum IgE and a reduction of IgE+ cells in the airway mucosa. The mean percentage sputum eosinophil count decreased significantly (p < 0.001) from 6.6 to 1.7% in the omalizumab group, a reduction significantly (p = 0.05) greater than with placebo (8.5 to 7.0%). This was associated with a significant reduction in tissue eosinophils; cells positive for the high-affinity Fc receptor for IgE; CD3+, CD4+, and CD8+ T lymphocytes; B lymphocytes; and cells staining for interleukin-4, but not with improvement in airway hyperresponsiveness to methacholine. This study shows antiinflammatory effects of omalizumab treatment and provides clues for mechanisms whereby omalizumab reduces asthma exacerbations and other asthma outcomes in more severe asthma. The lack of effect of omalizumab on methacholine responsiveness suggests that IgE or eosinophils may not be causally linked to airway hyperresponsiveness to methacholine in mild to moderate asthma.

Adult↗
PubMed2004

The splicing and fate of ADAM33 transcripts in primary human airways fibroblasts.

The ADAM (A Disintegrin and Metalloprotease) family of Zn++-dependent metalloproteases are multidomain proteins involved in diverse cellular activities. Polymorphic variation in ADAM33 is strongly associated with asthma and bronchial hyperresponsiveness. Identification of those isoforms of ADAM33 that are expressed in airways is fundamental to dissecting the role of ADAM33 in asthma. Analysis of primary human airways fibroblasts has shown the presence of a number of alternatively spliced forms of ADAM33, including one encoding a putative secreted variant, and many transcripts lacking the metalloproteinase domain. The relative abundance of these transcripts has been quantified using reverse transcription real-time polymerase chain reaction, in both nuclear and cytoplasmic fractions of RNA. These results demonstrate that a number of splice variants of ADAM33 are transported into the cytoplasm. Ninety percent of ADAM33 mRNA is retained in the nucleus and the subtle differences in the composition of nuclear and cytoplasmic RNA suggest important events in the splicing and selection of ADAM33 transcripts. Western blot analysis confirmed that several protein isoforms of ADAM33 are expressed in primary airways fibroblasts. These findings demonstrate that ADAM33 exists in multiple isoforms, suggesting that it is a complex molecule that plays multiple roles within mesenchymal cells.

ADAM Proteins↗
PubMed2004

Role of tumor necrosis factor alpha in asthma.

Asthma is a heterogeneous disease in which various cytokines orchestrate airway inflammation. Tumor necrosis alpha (TNF-alpha) is a proinflammatory cytokine that has been implicated in the modulation of inflammation in various diseases, including asthma. Although TNF-alpha blocking strategies have been an effective therapeutic modality in diseases such as rheumatoid arthritis, their role in asthma and the effects of the blockade in asthma is poorly understood. This article examines the role of TNF-alpha in asthma and the effects of blocking TNF-alpha as a possible therapeutic option in patients with severe corticosteroid-dependent asthma.

Asthma↗
PubMed2004

Induction of the epidermal growth factor receptor and its ligands in nasal epithelium by ozone.

BACKGROUND: Ozone is a photochemical oxidant pollutant that is an important public health hazard. Although the inflammatory response that occurs in response to ozone inhalation is well characterized, the mechanisms underlying epithelial cell activation are not well understood. OBJECTIVE: Because the epidermal growth factor receptor (EGFR) is a central regulator of epithelial function, we tested the hypothesis that nasal epithelial cells respond to ozone-induced oxidant stress by modulating expression of the EGFR and its ligands, EGF and transforming growth factor-alpha (TGF-alpha). METHODS: Normal volunteers were exposed to air or 400 parts per billion ozone for 2 hours, and then nasal biopsy specimens were harvested 6 hours later for immunohistochemical analysis of EGFR, EGF, and TGF-alpha. Nasal epithelial cell cultures were exposed in vitro to ozone or TNF-alpha; mediator release was measured by ELISA and cellular EGFR expression by immunoblotting and fluorescence-activated cell sorting analysis. RESULTS: Epithelial expression of the EGFR, EGF, and TGF-alpha were all significantly (P <.05) increased in the nasal biopsy specimens after ozone exposure, and there was a significant positive correlation between EGFR expression and the increase in neutrophil numbers in the nasal epithelium (P =.001, rho = 0.87). In vitro exposure of primary nasal epithelial cell cultures to ozone had no effect on EGFR expression, even though IL-8 release was enhanced. In contrast, exposure to TNF-alpha caused EGFR levels to increase significantly. CONCLUSION: These data suggest that the ozone-induced increase in EGFR expression observed in vivo is indirect, perhaps mediated by neutrophil-derived TNF-alpha.

Adult↗
PubMed2004

Genetics.

Explore the source record for details and available documents.

Asthma↗
PubMed2004

ADAM 33 and its association with airway remodeling and hyperresponsiveness in asthma.

Asthma is known to be a Th2 inflammatory syndrome that leads to intermittent airway obstruction. However, the mechanisms involved in development of the clinical features remain enigmatic, although genetic elements clearly are involved. Recently, based on a large genome wide screen involving families in the United Kingdom and the United States with at least two siblings with asthma, a locus was identified that encoded for a family of proteases. This group of proteins is now known as the ADAM superfamily. In this review, we discuss the ADAM superfamily and, in particular, ADAM 33, a member of a family of genes which encode a subgroup of zinc dependent metalloproteinase (metzincin). The potential for therapeutic intervention with ADAM 33 is extremely attractive and further work will not only focus on the specific domains of ADAM 33, but also the mechanisms by which they lead to bronchial hyperreactivity.

ADAM Proteins↗
PubMed2004

Epithelial-mesenchymal communication in the pathogenesis of chronic asthma.

Although Th-2-mediated inflammation is a key therapeutic target in asthma, its relationship to altered structure and functions of the airways is largely unknown. In addition to inflammation, asthma is a disorder involving the airway epithelium that is more vulnerable to environmental injury and responds to this by impaired healing. This establishes a chronic wound scenario that is capable of sustaining chronic inflammation as well as remodeling. This response occurs as a consequence of activation of the epithelial-mesenchymal unit, involving reciprocal activities of growth factors belonging to the fibroblast growth factor, epidermal growth factor, and transforming growth factor-beta families. The observation that structural changes in the airways in children at or before the onset of asthma occurs irrespective of inflammation might suggest that premodeling is required before Th-2 inflammatory responses can be sustained. Once established, altered function of constitutive airway cells, including fibroblasts, smooth muscle, nerves, and the epithelium, provides an abnormal microenvironment in which to generate a separate set of signals that underpin the acute/subacute inflammation characteristic of asthma exacerbations, triggered by viruses, pollutants, and allergens.

Asthma↗
PubMed2004

New strategies in the treatment and prevention of allergic diseases.

Allergic diseases (AD) are more prevalent today than 30 years ago but over the same period, few novel efficacious drugs have been discovered to treat, control or even cure these disorders. Topical or systemic glucocorticosteroids combined with symptom-relieving medications, such as beta 2 -adrenoceptor agonists, leukotriene inhibitors or antihistamines, are still the mainstay of antiallergic treatment. Modified glucocorticosteroids with less adverse effects, better bronchodilators and new selective mediator inhibitors may improve symptom control in the future. Only specific immunotherapy has shown potential for long-lasting disease-modifying effects. Immunomodulation is a therapeutic goal, aiming to modify the dominant helper T cell Type 2 inflammation to a helper T cell Type 1 response using modified allergens, mycobacteria or CpG oligodeoxynucleotides. Humanised monoclonal anti-IgE antibodies are an exciting new immunomodulatory medication that are expected to reach the clinical practice and have recently been licensed in Australia and the US. Advances in molecular, cellular and genetic research of the immunopathophysiology of AD have led to the development of new antagonists for cytokines, chemokines, receptors, second messengers and transcription factors that may become available for clinical use in the next 10 years. Specific diets supplemented with antioxidants or probiotics need further study but offer promise as safe and cheap preventative medicine. The strong genetic component of AD and the Human Genome Project have opened a new field of research, and modification or replacement of target genes has a curative potential with exciting new therapeutic developments in the years ahead.

Anti-Inflammatory Agents↗
PubMed2003

The role of ADAM33 in the pathogenesis of asthma.

While asthma is a disorder of the conducting airways characterised by Th2-directed inflammation, a second set of mechanisms is being increasingly recognised as fundamental to disease chronicity and severity, for which the term "remodelling" has been used. The cellular and mediator responses underpinning airway remodelling involve aberrant communication between the airway epithelium and underlying mesenchyme, involving the generation of growth factors that lead to proliferation of fibroblasts and smooth muscle and the deposition of matrix proteins to cause airway wall thickening linked to bronchial hyperresponsiveness and fixed airflow obstruction. The identification of ADAM33 on chromosome 20p13 from positional cloning as a novel candidate gene involved in the pathogenesis of these structural and functional changes has opened the way to further insight into these processes that contribute to corticosteroid refractoriness. The preferential expression of ADAM33 in mesenchymal cells and its multiple molecular actions provide ample opportunity for incriminating this molecule in chronic asthma. Its association with progressive asthma and in predicting reduced lung function in young children suggest that ADAM33 has an important role in the natural history and possibly the origins of asthma, a disease unique to humans.

ADAM Proteins↗
PubMed2003

Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial.

OBJECTIVES: To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone. Design and setting A 52 week, two period, double blind, multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were randomised to add montelukast or salmeterol. PARTICIPANTS: Patients (15-72 years; n = 1490) had a clinical history of chronic asthma for > or = 1 year, a baseline forced expiratory volume in one second (FEV1) value 50-90% predicted, and a beta agonist improvement of > or = 12% in FEV1. MAIN OUTCOME MEASURES: The primary end point was the percentage of patients with at least one asthma exacerbation. RESULTS: 20.1% of the patients in the group receiving montelukast and fluticasone had an asthma exacerbation compared with 19.1% in the group receiving salmeterol and fluticasone; the difference was 1% (95% confidence interval -3.1% to 5.0%). With a risk ratio (montelukast-fluticasone/salmeterol-fluticasone) of 1.05 (0.86 to 1.29), treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone. Salmeterol and fluticasone significantly increased FEV1 before a beta agonist was used and morning peak expiratory flow compared with montelukast and fluticasone (P < or = 0.001), whereas FEV1 after a beta agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups. Montelukast and fluticasone significantly (P = 0.011) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone. Both treatments were generally well tolerated. CONCLUSION: The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol.

Acetates↗
PubMed2003

Inflammatory cytokines can enhance CD44-mediated airway epithelial cell adhesion independently of CD44 expression.

In airways, the cell surface molecule CD44 is upregulated on bronchial epithelial cells in areas of damage. We have shown that a blocking standard CD44 (CD44s) antibody caused a 77% (+/- 19%) inhibition of cell migration at 3 h after mechanical damage and decreased epithelial cell repair of cells grown on cell culture filter inserts. With the use of primary human bronchial epithelial cells and the bronchial epithelial cell line 16HBE 14o-, a CD44s antibody inhibited >95% (P < 0.01) of cell binding to hyaluronic acid (HA). The cytokines TNF-alpha, IFN-gamma, IL-1 beta, and IL-4 stimulated a 2- to 3.5-fold increase in CD44-dependent cell binding to HA. IFN-gamma treatment did not increase CD44 expression as assessed by flow cytometry, although phorbol myristate acetate treatment did. This indicates that IFN-gamma-induced cell binding to HA did not require increased CD44 expression. These data indicate that CD44 is important for bronchial epithelial cell binding to HA and that cytokines known to be expressed in inflammation can increase HA binding independently of the level of CD44 expression.

Adjuvants, Immunologic↗
PubMed2003

Enzyme potentiated desensitisation in treatment of seasonal allergic rhinitis: double blind randomised controlled study.

OBJECTIVE: To assess the efficacy of enzyme potentiated desensitisation in the treatment of severe summer hay fever poorly controlled by pharmacotherapy. DESIGN: Double blind randomised placebo controlled parallel group study. SETTING: Hospital in Hampshire. PARTICIPANTS: 183 participants aged between 18 and 64 with a history of severe summer hay fever for at least two years; all were skin prick test positive to timothy grass pollen. 90 randomised to active treatment; 93 randomised to placebo. INTERVENTIONS: Active treatment: two injections of enzyme potentiated desensitisation, given between eight and 11 weeks apart, each comprising 200 Fishman units of beta glucuronidase, 50 pg 1,3-cyclohexanediol, 50 ng protamine sulphate, and a mixed inhaled allergen extract (pollen mixes for trees, grasses, and weeds; allergenic fungal spores; cat and dog danders; dust and storage mites) in a total volume of 0.05 ml of buffered saline. Placebo: two injections of 0.05 ml buffered saline solution. MAIN OUTCOME MEASURES: Proportion of problem-free days; global rhinoconjunctivitis quality of life scores assessed weekly during pollen season. RESULTS: The active treatment group and the placebo group did not differ in the proportion of problem-free days, quality of life scores, symptom severity scores, change in quantitative skin prick provocation threshold, or change in conjunctival provocation threshold. No clinically significant adverse reactions occurred. CONCLUSIONS: Enzyme potentiated desensitisation showed no treatment effect in this study.

Adult↗
PubMed2003

Personal exposure to nitrogen dioxide (NO2) and the severity of virus-induced asthma in children.

BACKGROUND: A link between exposure to the air pollutant nitrogen dioxide (NO2) and respiratory disease has been suggested. Viral infections are the major cause of asthma exacerbations. We aimed to assess whether there is a relation between NO2 exposure and the severity of asthma exacerbations caused by proven respiratory viral infections in children. METHODS: A cohort of 114 asthmatic children aged between 8 and 11 years recorded daily upper and lower respiratory-tract symptoms, peak expiratory flow (PEF), and measured personal NO2 exposures every week for up to 13 months. We took nasal aspirates during reported episodes of upper respiratory-tract illness and tested for infection by common respiratory viruses and atypical bacteria with RT-PCR assays. We used generalised estimating equations to assess the relation between low (<7.5 microg/m3), medium (7.5-14 microg/m3 ), and high (>14 microg/m3) tertiles of NO2 exposure in the week before or after upper respiratory-tract infection and the severity of asthma exacerbation in the week after the start of an infection. FINDINGS: One or more viruses were detected in 78% of reported infection episodes, and the medians of NO2 exposure were 5 (IQR 3.6-6.3), 10 (8.7-12.0), and 21 microg/m3 (16.8-42.9) for low, medium, and high tertiles, respectively. There were significant increases in the severity of lower respiratory-tract symptom scores across the three tertiles (0.6 for all viruses [p=0.05] and >2 for respiratory syncytial virus [p=0.01]) and a reduction in PEF of more than 12 L/min for picornavirus (p=0.04) for high compared with low NO2 exposure before the start of the virus-induced exacerbation. INTERPRETATION: High exposure to NO2 in the week before the start of a respiratory viral infection, and at levels within current air quality standards, is associated with an increase in the severity of a resulting asthma exacerbation.

Air Pollutants↗
PubMed2003

Rhinovirus is not detectable in peripheral lung tissue after asthma death.

OBJECTIVE: Viral infections are associated with both mild and severe exacerbations of asthma and may therefore be associated with asthma death. As such we hypothesized that it might be possible to detect rhinovirus (RV), the virus most frequently implicated in acute asthma, in lung tissue from patients who died from asthma. METHODOLOGY: We studied archival, wax-embedded lung tissue obtained postmortem from: (i) patients who died from asthma (n = 12), (ii) asthma patients with non-asthma-related death (n = 3), and (iii) non-asthmatic individuals who died from unrelated causes (n = 3). A validated reverse transcription-polymerase chain reaction (RT-PCR) assay was used to detect RV. To confirm RNA preservation, RT-PCR was used to detect expression of the constitutive gene adenine-phosphoribosyl-transferase (APRT). Sensitivity of the assay was assessed using wax-embedded RV-infected cells. RESULTS: Sensitivity of RT-PCR for RV in wax-embedded sections was similar to previous studies (approximately 100 viral copies). Specimens used for study were predominantly of alveolar and small airway origin (< 2 mm). All tissues examined were negative for the presence of RV mRNA and positive for APRT mRNA. CONCLUSIONS: RV infection of the lower airway may be an uncommon cause of fatal asthma. Alternatively, RV may not extend to peripheral airways and more proximal tissue sampling or PCR assays for other viruses may be required to determine an association between viral respiratory tract infection and fatal asthma.

Adolescent↗