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Biomedical subjects

S Holgate

Publications and source records attributed to S Holgate.

At least 37 records · Page 2Linked to original sources
PubMed1997

Cultured nasal polyps from nonatopic and atopic patients release RANTES spontaneously and after stimulation with phytohemagglutinin.

BACKGROUND: Eosinophil infiltration of tissue is a hallmark of nasal polyposis in both nonatopic and atopic patients. These cells are thought to play a key role in the nasal polyp inflammatory process. OBJECTIVE: The objective of this study was to investigate whether cultured nasal polyps derived from nonatopic and atopic patients release RANTES both spontaneously and after phytohemagglutinin (PHA) stimulation. METHODS: Nasal polyps were obtained from 12 subjects (6 nonatopic and 6 atopic), cut into 2 to 3 mm large specimens, and cultured for 48 hours with or without PHA. RANTES was measured in the culture supernatant by ELISA (R&D Systems, U.K.). RESULTS: Immunoreactive RANTES was found to be present in the culture supernatant of nasal polyps derived from both nonatopic and atopic patients with no difference between the two groups (median: 3.8 vs 2.9 pg/mg/ml). On incubation with PHA, nasal polyps from both nonatopic and atopic patients released sevenfold and 11-fold greater amounts of RANTES than unstimulated samples. As determined by immunohistochemistry, RANTES was localized to the vascular endothelium in nasal polyps from both groups of patients. CONCLUSIONS: This study demonstrates that cultured nasal polyps derived from both nonatopic and atopic patients release RANTES spontaneously and after PHA stimulation. This observation and the finding that RANTES is present in nasal polyp endothelial cells suggest that this chemokine may be an important mediator of eosinophil and lymphocyte recruitment in both nonatopic and atopic nasal polyposis.

Adult↗
PubMed1997

The effect of treatment with oral corticosteroids on asthma symptoms and airway inflammation.

To improve understanding of the mechanisms of action of oral corticosteroids in asthma, we have conducted a double-blind, placebo-controlled study with prednisolone (20 mg for 2 wk followed by 10 mg for 4 wk) or placebo in 14 and 13 atopic corticosteroid-naive asthmatic subjects, respectively. Before and after treatment subjects underwent bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsy. Treatment with prednisolone, but not placebo, significantly reduced asthma symptoms (from mean +/- SEM total weekly score of 34 +/- 6.2 to 15.7 +/- 3.2, p = 0.02) and albuterol usage (from mean +/- SEM number of puffs/wk of 29.7 +/- 6.2 to 18.2 +/- 3.7, p = 0.01) and significantly increased FEV1 (from 89.8 +/- 4.4% to 99.3 +/- 4.1% of predicted, p = 0.03). There were no significant changes in inflammatory or epithelial cell counts, levels of T-cell activation or albumin concentration in BAL. However, immunohistochemistry of bronchial biopsies showed that in the submucosa prednisolone significantly decreased numbers of mast cells by 62% (from median 45 to 17/mm2, p = 0.01), eosinophils by 81% (from median 30.1 to 5.7/mm2, p = 0.004), and CD4+ T-cells by 68% (from median 64.6 to 18.5/mm2, p = 0.02). In the epithelium only the reduction in the numbers of eosinophils was significant (from median 1.1 to 0/mm of epithelium, p = 0.02). There were no significant changes in any cell counts in the subjects receiving placebo, and comparison of the changes between the treatment groups identified a significant prednisolone-related reduction in submucosal eosinophil and mast cell counts (p = 0.003 and 0.03, respectively). The temporal association between the clinical and physiologic improvement, and the correlation between the magnitude of change in CD4+ T-cell counts in the submucosa and increase in PC20 methacholine (rs = 0.60, p = 0.049) suggests that the reduction in airways inflammatory cell numbers underlies the clinical efficacy of oral corticosteroids.

Administration, Oral↗
PubMed1997

Short-term ozone exposure upregulates P-selectin in normal human airways.

Short-term exposure to ambient levels of ozone induces neutrophilic bronchitis. To investigate the early events contributing to inflammatory cell recruitment in the airways we exposed 12 healthy nonsmoking volunteers to 0.12 ppm ozone or filtered air for 2 h on two separate occasions. Spirometry and fiberoptic bronchoscopy were performed immediately and at 1.5 h after the two exposures, respectively. Total protein, albumin, and total and differential cell counts were performed on the bronchial wash and BAL fluid. Bronchial biopsies were embedded in glycol methacrylate and immunostained for inflammatory cells, including neutrophils, mast cells, total T-cells (CD3), T-cell subset CD8, and leukocyte endothelial adhesion molecules, including VCAM-1, ICAM-1, E-selectin, and P-selectin. No significant changes were observed in FEV1, FVC, or any inflammatory indices in the bronchial wash and BAL fluid. In addition, no significant differences were seen in inflammatory cell numbers or percentages of vessels expressing VCAM-1, E-selectin, or ICAM-1 in the biopsies. The percentage of vessels expressing P-selectin increased significantly after ozone exposure: p = 0.016; median (IQR), 28.76 (26.36-36.94) versus 47.06 (38.14-56.86)%. The upregulation of P-selectin could signify an early inflammatory response to ozone such as margination and rolling of the neutrophils on the vessel wall prior to transendothelial migration.

Adult↗
PubMed1997

Effects of ozone on epithelium and sensory nerves in the bronchial mucosa of healthy humans.

Neuropeptides released from sensory nerves during inflammation have potent effects on bronchomotor tone, airway secretion, and inflammatory cells. We investigated the effects of ozone on sensory nerves by exposing 12 healthy, nonsmoking subjects to 0.2 ppm ozone and filtered air (FA) for 2 h on separate occasions, with intermittent exercise and rest. Spirometry was performed at baseline and 15 min after exposures, and bronchoscopy (bronchial biopsy and bronchoalveolar lavage [BAL]) was done 6 h after exposure. Frozen sections were immunostained for the anatomic neural marker protein gene peptide (PGP) 9.5 and the sensory neutropeptides substance P (SP) and calcitonin-gene-related peptide (CGRP). Nerves in the submucosa were quantified by image analysis. A trend toward an increase in the levels of polymorphonuclear leukocytes (PMNs) (air versus ozone, median [interquartile range]: 3.5 [2 to 5.3%] versus 9.8 [4.2 to 16.3%], p = 0.07) and ciliated epithelial cells (median [interquartile range]: 1.6 [1.3 to 3.4%] versus 5 [2.2 to 9.8%], p = 0.05) was observed in the BAL fluid (BALF). There was a significant decrease in SP immunoreactivity following ozone exposure (median [interquartile range]: 0.6 [0.05 to 1.2] versus 0.15 [0.08 to 0.18], p < 0.05). A significant inverse correlation was observed between SP immunoreactivity and: (1) percent PMNs and ciliated epithelial cells in the BALF; and (2) percent change in FEV1 following exposure to ozone. These findings indicate that short-term exposure to 0.2 ppm ozone causes epithelial shedding and stimulates subepithelial sensory nerves to release SP into the airways. The release of SP could contribute to bronchoconstriction and subsequent neutrophil infiltration into the airways.

Adult↗
PubMed1996

Eosinophil recruitment following allergen challenge is associated with the release of the chemokine RANTES into asthmatic airways.

Eosinophil infiltration of the airways in response to allergen exposure is a characteristic of bronchial asthma. However, the mechanisms by which these cells are recruited are poorly understood. We have investigated the presence of eosinophil chemotactic activity (ECA) in bronchoalveolar lavage fluid obtained from allergic asthmatics (n = 6) 4 h after endobronchial allergen challenge. ECA was purified by sequential heparin affinity chromatography and reverse-phase HPLC. A single peak of ECA was detected; SDS-PAGE and Western blot analysis showed that the peak contained a protein of 8 kDa and corresponded to the chemokine RANTES (regulated upon activation, normal T cell expressed and secreted). Consistent with this, the ECA was neutralized by an Ab to RANTES. Measurement of RANTES by ELISA in 10x concentrated bronchoalveolar lavage fluid showed increased levels of this chemokine at the allergen site (median, 187 pg/ml; range, 46-263 pg/ml) in comparison with a saline challenge control site (median, 32.5 pg/ml; range, 11-94 pg/ml), P < 0.005. Furthermore, there was a significant correlation between concentrations of immunoreactive RANTES and the number of eosinophils at the allergen challenge site (r = 0.8; p < 0.001), but not at the saline site (r = 0.2; p = 0.12). These results suggest that RANTES in involved in the recruitment of eosinophils into the asthmatic airways after allergen challenge.

Adult↗
PubMed1996

Phenotypic characterization of T cells infiltrating the conjunctiva in chronic allergic eye disease.

BACKGROUND: Chronic allergic conjunctivitis comprises a spectrum of diseases including atopic keratoconjunctivitis, atopic blepharoconjunctivitis, vernal keratoconjunctivitis, and contact lens-associated giant pupillary conjunctivitis. Each condition is characterized by a complex immunopathology with a mixed cellular infiltrate. Treatment with conventional mast cell stabilizers is often unsatisfactory, and therapy depends heavily on topical corticosteroids. OBJECTIVE: Recent evidence suggests that T lymphocytes play an important role in mediating the immunopathology seen in the chronic allergic response in the skin and the lungs. METHODS: We have therefore investigated the prevalence of T cells and their subsets in the different chronic allergic eye conditions by means of immunohistochemistry. RESULTS: We found significantly increased numbers of CD4+, CD45RO+, and HLA-DR+ T cells in the conjunctiva of patients with atopic and vernal keratoconjunctivitis and giant papillary conjunctivitis, with a corresponding upregulation of markers present on antigen presenting cells. CONCLUSIONS: These findings suggest that like allergic conditions in the skin and lungs, CD4+ memory T cells are involved in the regulation of the immunopathology of chronic allergic eye responses. Further characterization of these T cells will provide the information necessary for future immunotherapeutic interventions.

Adolescent↗
PubMed1996

Osteocalcin, growth, and inhaled corticosteroids: a prospective study.

OBJECTIVES: To determine the relationship between biochemical markers of bone metabolism and statural growth, and their suitability as surrogate markers of inhaled corticosteroid induced growth suppression. DESIGN: Randomised, double blind, placebo controlled comparison of inhaled beclomethasone dipropionate 200 micrograms twice daily as dry powder for six months. SETTING: Southampton. OUTCOME MEASURES: Serum osteocalcin, urinary deoxypyridinoline, and statural growth. SUBJECTS: 7 to 9 year old children with recurrent wheeze. RESULTS: There were no significant differences in serum osteocalcin between the beclomethasone dipropionate and placebo group measured at baseline or after three and six months' treatment, while deoxy-pyridinoline was significantly higher in the placebo treated children after three months. Growth was significantly decreased in the beclomethasone dipropionate group over the course of the study. Growth over the six months, both in those receiving beclomethasone dipropionate and those receiving placebo, was significantly correlated with serum osteocalcin measured at three months and six months. CONCLUSION: Although serum osteocalcin shows excellent correlation with growth, it is a poor marker for decreased growth associated with use of inhaled corticosteroids.

Administration, Inhalation↗
PubMed1993

Investigative use of fibreoptic bronchoscopy for local airway challenge in asthma.

Local airway challenge has advantages over inhalation bronchial challenge as the response of the airway can be restricted and directly observed. It has been safely performed in subjects with mild or moderate asthma, either by the direct instillation of challenge solution to the selected segmental airways via a bronchoscope, or delivered to an airway segment isolated with a double-balloon catheter. However, these techniques carry potential complications, such as generalized wheeze, and due care is required in selection of subjects. Most investigators have used the method for studying the airway events following allergen challenge. Others have studied the airway changes following challenge with non-allergen provocation agents, such as hypertonic saline, adenosine 5'-monophosphate and cold dry air. The method has helped to define changes in the inflammatory cells and mediators in relation to early and late airway responses to allergen. Similarly, study of airway events following local challenge with hypertonic solution has provided useful knowledge in understanding the mechanisms of exercise-induced asthma. With more experience and an improved margin of safety, it will be possible to study local changes in airway physiology following local airway challenge. Finally, the techniques also have potential use for studying the airway events following provocation with a wide range of agents of potential relevance to the pathogenesis of asthma.

Allergens↗
PubMed1991

Respiratory symptoms in children at schools near a foundry.

A survey was carried out in response to complaints of increased respiratory symptoms in children at schools near a foundry in Walsall, West Midlands. Air monitoring around the factory had shown concentrations of formaldehyde most of which were orders of magnitude below the current occupational exposure limit of 2.5 mg/m3, although concentrations up to 0.3 mg/m3 had been recorded over short periods. The study sample comprised children aged 6.8-7.8 years from 39 schools in the borough. Information about respiratory symptoms and potential risk factors for respiratory disease was elicited from parents by a self administered questionnaire. Data were obtained on 1334 children, a response rate of 81.8%. The prevalences of reported wheeze (11.1%), breathlessness (7.7%), and chest discomfort (8.6%) were similar to those in an earlier survey carried out in Southampton by the same method at the same time of year. Cough (prevalence = 18.4%) and chestiness at night (14.6%) were significantly less common than in Southampton. When sex, social class, housing tenure, passive smoking, and parental history of asthma were taken into account, the prevalences of symptoms at schools within one mile of the foundry were generally lower than in other parts of Walsall. These findings give no support to the hypothesis that foundry emissions cause respiratory disease in children, although an adverse effect in a few sensitive children cannot be ruled out.

Air Pollution↗
PubMed1989

A scientific basis to the treatment of allergic diseases.

The underlying mechanisms of allergic diseases are understood better than ever before. This knowledge provides the basis for a rational approach to the choice of medication and effective research into the development of more specific pharmacological agents.

Histamine H1 Antagonists↗
PubMed1988

Effect of methacholine induced bronchoconstriction on the pulmonary distribution and plasma pharmacokinetics of inhaled sodium cromoglycate in subjects with normal and hyperreactive airways.

Inhalation treatment may be less effective in the presence of bronchoconstriction because of the reduced penetration of drugs into the airways. The effect of bronchoconstriction on the lung deposition and plasma pharmacokinetics of inhaled sodium cromoglycate was examined. Ten subjects attended the laboratory on three occasions. On the first occasion a bronchial provocation test was performed to determine the concentration of methacholine required to reduce the forced expiratory volume in one second (FEV1) by 20% (PC20). On the two subsequent occasions subjects inhaled either saline or their PC20 methacholine, followed five minutes later by an aerosol containing sodium cromoglycate and stannous phytate labelled with technetium-99m. Twenty minutes later a gamma emission lung scan was performed to determine the intrathoracic deposition of the nebulised aerosol. The central:peripheral (C:P) ratio of lung deposition was then calculated. Measurements of FEV1 were made and blood samples taken for analysis of plasma sodium cromoglycate concentration at intervals for four hours. Methacholine led to a 23.4% (SEM 0.6%) lower FEV1 and a 2.8 times higher C:P ratio than those observed after saline. There was a direct correlation between log PC20 methacholine and the increase in the C:P ratio (r = 0.81). Despite these changes with methacholine, the plasma pharmacokinetics of inhaled sodium cromoglycate were not significantly different after methacholine and after saline, except that the maximum concentration achieved (Cmax) was increased. These observations suggest that the area of cromoglycate deposition and the anatomical site are less important in determining the plasma pharmacokinetics of cromoglycate than is the total dose delivered to the lung.

Administration, Inhalation↗
PubMed1987

The role of histamine in allergen and adenosine-induced bronchoconstriction.

We have investigated the role of histamine in allergen and adenosine-5'-monophosphate (AMP)-induced bronchoconstriction in asthmatic subjects by performing inhalation challenge tests with histamine, AMP and allergen after treatment with placebo or the potent H1 histamine receptor antagonist, terfenadine. Single concentrations of each agonist which had previously been shown to produce a 30% fall in FEV1 were used. After placebo, AMP and histamine both produced rapid bronchoconstriction reaching a maximum within 5 min and returning to within 10% of baseline after 25 min. Terfenadine inhibited this reaction to histamine completely and to AMP by 86%. The response to allergen was slower in onset and was sustained over 45 min and was inhibited 50% by terfenadine. We interpret these results as reflecting the contribution of histamine to the various airway challenges, both histamine and newly generated mediators comprise the response to allergen, whereas AMP selectively enhances mast cell degranulation without affecting the production of arachidonic acid derived mediators.

Adenosine Monophosphate↗
PubMedDate not supplied

Induction of nitric oxide synthase in asthma.

Nitric oxide (NO) is a mediator of vasodilatation and bronchodilatation synthesised from L-arginine by the enzyme NO synthase, which is either constitutive or induced by lipopolysaccharides and/or cytokines. The presence and function of NO synthase in normal or diseased lung is not yet clear. Asthma is characterised by bronchial hyperresponsiveness, epithelial damage, inflammation, and increased cytokine production. To investigate the presence of NO synthase in asthma, we immunostained bronchial biopsies from non-steroid-treated people with asthma and non-asthmatic controls with specific polyvalent antisera to purified inducible NO synthase and to a selected peptide sequence of the same enzyme. Immunoreactivity was seen in the epithelium and some inflammatory cells in 22 of 23 biopsies from people with asthma, but in only 2 of 20 controls. To assess the relation of cytokines to NO synthase induction, bronchial epithelial cells in culture were stimulated with tumour necrosis factor (TNF alpha). Inducible enzyme immunoreactivity was found only in the treated cells. The existence of inducible NO synthase in human lungs suggests that increased production of NO, probably induced by cytokines, may be relevant to the pathology of asthma.

Adult↗