Biomedical subjects

Andrew J Wardlaw

Publications and source records attributed to Andrew J Wardlaw.

10 recordsLinked to original sources

PubMed2003

Associations between polymorphisms of the high-affinity immunoglobulin E receptor and late-onset airflow obstruction in older populations.

OBJECTIVES: To test the hypothesis that genetic polymorphisms in the beta subunit of the high-affinity immunoglobulin E (IgE) receptor are associated with late-onset airflow obstruction. DESIGN: Case-control candidate gene association study. SETTING: Department of Medicine for the Elderly and Respiratory Medicine in three teaching hospitals in Leicester and Manchester, United Kingdom. PARTICIPANTS: Cases with late-onset airflow obstruction with age-, sex-, and geographically matched controls. MEASUREMENTS: Subjects were genotyped for two polymorphisms of the beta subunit of the high-affinity IgE receptor (RsaI intron 2 and RsaI exon 7). The association between the polymorphisms and phenotypes was examined using contingency tables and linear regression models. RESULTS: Two hundred eighty-three cases and 144 controls were genotyped. RsaI exon 7 AA was associated with eczema (odds ratio (OR)=2.27, 95% confidence interval (CI)=1.17-4.38, P=.015). No other associations were found. Total serum IgE levels were significantly higher in cases than controls (adjusted OR for high/low IgE=2.56, 95% CI=1.53-4.28, P<.001). CONCLUSION: Serum IgE levels, but not the high-affinity IgE receptor polymorphisms, were associated with late-onset airflow obstruction, suggesting that interaction between environmental and genetic factors controlling serum IgE levels and disease pathogenesis may differ between early- and late-onset airflow obstruction phenotypes.

Age Factors↗

PubMed2003

Expression of and functional responses to protease-activated receptors on human eosinophils.

Eosinophil recruitment to airway tissue is a key feature of asthma, and release of a wide variety of toxic mediators from eosinophils leads to the tissue damage that is a hallmark of asthma pathology. Factors that control the release of these toxic mediators are targets for potential therapeutic intervention. Protease-activated receptors (PARs) are a novel class of receptors that are activated by cleavage of the N terminus of the receptor by proteases such as thrombin or trypsin-like enzymes. To date, PAR1-4 have been identified, and there are several studies that have demonstrated the expression of PARs in airway tissue, particularly the respiratory epithelium. We have investigated whether eosinophils express PARs and if activation of these receptors will then trigger a functional response. Using a combination of reverse transcriptase-polymerase chain reaction, Western blotting, and flow cytometry analysis, we have demonstrated that eosinophils express PAR1 and PAR2. FACS analysis showed that PAR1 could be clearly detected on the surface of the cells, whereas PAR2 appeared to be primarily intracellular. Trypsin and the PAR2 agonist peptide were seen in trigger shape change, release of cysteinyl leukotrienes, and most obviously, generation of reactive oxygen species. In contrast, thrombin had no effect on eosinophil function. The PAR1 agonist peptide did have a minor effect on eosinophil function, but this was most likely down to its ability to activate PAR1 and PAR2. These results demonstrate that PAR2 is the major PAR receptor that is capable of modulating eosinophil function.

Asthma↗

PubMed2002

Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.

BACKGROUND: Treatment decisions in asthma are based on assessments of symptoms and simple measures of lung function, which do not relate closely to underlying eosinophilic airway inflammation. We aimed to assess whether a management strategy that minimises eosinophilic inflammation reduces asthma exacerbations compared with a standard management strategy. METHODS: We recruited 74 patients with moderate to severe asthma from hospital clinics and randomly allocated them to management either by standard British Thoracic Society asthma guidelines (BTS management group) or by normalisation of the induced sputum eosinophil count and reduction of symptoms (sputum management group). We assessed patients nine times over 12 months. The results were used to manage those in the sputum management group, but were not disclosed in the BTS group. The primary outcomes were the number of severe exacerbations and control of eosinophilic inflammation, measured by induced sputum eosinophil count. Analyses were by intention to treat. FINDINGS: The sputum eosinophil count was 63% (95% CI 24-100) lower over 12 months in the sputum management group than in the BTS management group (p=0.002). Patients in the sputum management group had significantly fewer severe asthma exacerbations than did patients in the BTS management group (35 vs 109; p=0.01) and significantly fewer patients were admitted to hospital with asthma (one vs six, p=0.047). The average daily dose of inhaled or oral corticosteroids did not differ between the two groups. INTERPRETATION: A treatment strategy directed at normalisation of the induced sputum eosinophil count reduces asthma exacerbations and admissions without the need for additional anti-inflammatory treatment.

Adult↗

PubMed2002

Clinical, radiologic, and induced sputum features of chronic obstructive pulmonary disease in nonsmokers: a descriptive study.

Epidemiologic studies show that 5-12% of subjects with chronic obstructive pulmonary disease (COPD) are nonsmokers. Little is known about the pathophysiology of the fixed airflow obstruction in these subjects. We have prospectively identified 25 patients with COPD who had never smoked or had a less than 5 pack years smoking history and present the clinical, radiologic, and induced sputum features. Our population represented 5.7% of total referrals with fixed airflow obstruction over 2 years. Patients had a mean age of 70 years, were predominantly female (86%), and had a mean duration of respiratory symptoms of 7 years. The mean FEV(1) was 58%, and the FEV(1)/FVC was 55%. Features on high-resolution computed tomographic scanning were nonspecific and were considered typical of a wider population with COPD. An induced sputum differential inflammatory cell count suggested the presence of two distinct groups. Nine had significant sputum eosinophilia (mean, 8.1%; normal, less than 1.9%), and the remaining 13 had a normal sputum eosinophil and tended to have a raised sputum neutrophil count (mean, 70.1%; normal, less than 65%). Organ-specific autoimmune disease was present in 7 of the 22 patients (32%) and was particularly prevalent in those without sputum eosinophilia (6 of 13). In conclusion, COPD in nonsmokers predominantly affects females and has at least two pathologic subgroups, one of which may be associated with organ-specific autoimmune disease. Further investigation of this group may disclose novel mechanisms of fixed airflow obstruction.

Aged↗

PubMed2002

Mast-cell infiltration of airway smooth muscle in asthma.

BACKGROUND: Asthma and eosinophilic bronchitis are characterized by similar inflammatory infiltrates in the submucosa of the lower airway. However, eosinophilic bronchitis differs from asthma in that there is no variable airflow obstruction or airway hyperresponsiveness in the former condition. We tested the hypothesis that there were differences between the two conditions in the microlocalization of mast cells within the airway smooth muscle. METHODS: Immunohistochemical analysis of bronchial-biopsy specimens was completed in 17 subjects with asthma, 13 subjects with eosinophilic bronchitis, and 11 normal controls recruited from two centers. RESULTS: Both groups with disease had a similar degree of submucosal eosinophilia and thickening of the basement membrane and lamina reticularis. By contrast, the number of tryptase-positive mast cells in the bundles of airway smooth muscle from subjects with asthma (median, 5.1 mast cells per square millimeter of smooth muscle [range, 0 to 33.3]) was substantially higher than that in subjects with eosinophilic bronchitis (median, 0 mast cells per square millimeter; range, 0 to 4.8) and that in normal controls (median, 0 mast cells per square millimeter [range, 0 to 6.4]; P<0.001 for the comparison among the three groups). T cells and eosinophils were not usually seen in the airway smooth muscle in any of the groups. CONCLUSIONS: The infiltration of airway smooth muscle by mast cells is associated with the disordered airway function found in asthma.

Adult↗

PubMed2002

Expression of the chemokine receptors CCR4, CCR5, and CXCR3 by human tissue-infiltrating lymphocytes.

Differential expression of adhesion molecules and chemokine receptors has been useful for identification of peripheral blood memory lymphocyte subsets with distinct tissue and microenvironmental tropisms. Expression of CCR4 by circulating memory CD4(+) lymphocytes is associated with cutaneous and other systemic populations while expression of CCR9 is associated with a small intestine-homing subset. CCR5 and CXCR3 are also expressed by discrete memory CD4(+) populations in blood, as well as by tissue-infiltrating lymphocytes from a number of sites. To characterize the similarities and differences among tissue-infiltrating lymphocytes, and to shed light on the specialization of lymphocyte subsets that mediate inflammation and immune surveillance in particular tissues, we have examined the expression of CCR4, CXCR3, and CCR5 on CD4(+) lymphocytes directly isolated from a wide variety of normal and inflamed tissues. Extra-lymphoid tissues contained only memory lymphocytes, many of which were activated (CD69(+)). As predicted by classical studies, skin lymphocytes were enriched in CLA expression whereas intestinal lymphocytes were enriched in alpha(4)beta(7) expression. CCR4 was expressed at high levels by skin-infiltrating lymphocytes, at lower levels by lung and synovial fluid lymphocytes, but never by intestinal lymphocytes. Only the high CCR4 levels characteristic of skin lymphocytes were associated with robust chemotactic and adhesive responses to TARC, consistent with a selective role for CCR4 in skin lymphocyte homing. In contrast, CXCR3 and CCR5 were present on the majority of lymphocytes from each non-lymphoid tissue examined, suggesting that these receptors are unlikely to determine tissue specificity, but rather, may play a wider role in tissue inflammation.

Antigens, Differentiation, T-Lymphocyte↗

PubMed2002

TH2 cytokine expression in bronchoalveolar lavage fluid T lymphocytes and bronchial submucosa is a feature of asthma and eosinophilic bronchitis.

BACKGROUND: Asthma is characterized by variable airflow obstruction and airway hyperresponsiveness in association with airway inflammation under the influence of T(H)2 cytokines. Eosinophilic bronchitis has similar immunopathology to asthma but without disordered airway physiology. Whether eosinophilic bronchitis is associated with increased expression of T(H)2 cytokines is unknown. OBJECTIVE: We sought to assess the expression of T(H)2 cytokines in eosinophilic bronchitis. METHODS: Expression of activation markers and chemokine receptors from blood and bronchoalveolar lavage (BAL) fluid T cells and the T(H)2 cytokine expression from these T cells and bronchial mucosa biopsy specimens were assessed from subjects with eosinophilic bronchitis, subjects with asthma, and healthy control subjects. RESULTS: The proportion of resting (stimulated) CD4 BAL fluid T cells expressing intracellular IL-4 was significantly higher in the subjects with eosinophilic bronchitis 7.2% (11.4%) and subjects with asthma 5.3% (5.5%) than in healthy control subjects 2.8% (3.9%) (P =.03). The number of IL-4(+) (P <.001) and IL-5(+) (P =.003) cells per square millimeter of bronchial submucosa was significantly higher in the disease groups than in the healthy control subjects. Expression of intracellular IFN-gamma was significantly higher in stimulated blood CD8 T cells from subjects with eosinophilic bronchitis (24%) and asthma (17%) than in the healthy control subjects (5%; P =.003). There were no between-group differences in expression of IFN-gamma in the BAL fluid T cells or in the bronchial submucosa and no differences in expression of activation markers or chemokine receptors. CONCLUSION: These findings support the concept of asthma as a disease associated with activation of T(H)2 lymphocytes in the airway and provide evidence that these cytokines play a role in the development of airway inflammation in eosinophilic bronchitis but suggest that the release of T(H)2 cytokines is not sufficient for the elaboration of disordered airway physiology in asthma.

Adult↗

PubMed2002

A comparison of the validity of different diagnostic tests in adults with asthma.

STUDY OBJECTIVES: Diagnosing asthma is not always easy, and there are times when objective tests can be helpful. The extent to which these tests alter the probability of asthma depends on how much more commonly the test result is positive in subjects with asthma compared to healthy subjects and particularly subjects with conditions that are commonly confused with asthma. We set out to compare the sensitivity and specificity of different tests in this setting. DESIGN: Single-center, cross-sectional, observational study. SETTING: Teaching hospital. PATIENTS: Twenty-one healthy control subjects, 69 patients with asthma, and 20 subjects referred to the hospital with a diagnosis of asthma who were found to have alternative explanations for their symptoms (i.e., pseudoasthma). INTERVENTIONS: We measured methacholine airway responsiveness, the maximum within-day peak expiratory flow amplitude mean percentage (derived from twice-daily readings for > 2 weeks), the FEV(1)/FVC ratio, the percentage change in FEV(1) 10 min after the administration of 200 microg inhaled albuterol, and the differential eosinophil count in blood and induced sputum. We derived normal ranges (from the 95% upper or lower limit for healthy subjects), sensitivity, and specificity (ie, the percentage of subjects with pseudoasthma who had negative test results). RESULTS: Most tests were less specific when the reference population was composed of subjects with conditions that can be confused with asthma. Methacholine airway responsiveness and the sputum differential eosinophil count were the most sensitive (91% and 72%, respectively) and specific (90% and 80%, respectively) tests. CONCLUSION: We conclude that methacholine airway responsiveness and the sputum differential eosinophil count are the most useful objective tests in patients with mild asthma.

Adolescent↗

PubMed2002

Eosinophils.

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Animals↗

PubMedDate not supplied

Duplicate publication.

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Duplicate Publications as Topic↗