Airway re-narrowing following deep inspiration in asthmatic and nonasthmatic subjects.

King GG.

Woolcock Institute of Medical Research and Cooperative Research Centre for Asthma, University of Sydney, Australia. cms woolcock.org.au

After bronchoconstriction, deep inspiration (DI) causes dilatation followed by airway re-narrowing. Re-narrowing may be faster in asthmatic than nonasthmatic subjects. This study investigated the relationship between re-narrowing and the magnitude of both DI-induced dilatation and the volume-dependence of respiratory system resistance (Rrs) during tidal breathing. In 25 asthmatic and 18 nonasthmatic subjects the forced oscillation technique was used to measure Rrs at baseline and after methacholine challenge, during 1 min of tidal breathing, followed by DI to total lung capacity (TLC) and passive return to functional residual capacity (FRC). Dilatation was measured as the decrease in Rrs between end tidal inspiration and TLC, re-narrowing as Rrs at FRC immediately after DI, as per cent Rrs at end-tidal expiration, and volume dependent tidal fluctuation as the difference between mean Rrs at end-expiration and end-inspiration. Asthmatic subjects had greater re-narrowing, less dilatation, and greater tidal fluctuations both at baseline and after challenge. Re-narrowing correlated with baseline tidal fluctuation and inversely with dilatation. Both baseline tidal fluctuation and dilatation were significant independent predictors of re-narrowing. Following deep inspiration-induced dilatation, faster airway re-narrowing in asthmatic than nonasthmatic subjects is associated not only with reduced deep inspiration-induced dilatation but also with some property of the airways that is detectable prior to challenge as an increased volume dependence of resistance.

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[The influence oc glycocorticoid therapy on sputum ECP concentration in symptomatic patients with bronchial asthma]

[Article in Polish]

Chazan R.

Klinika i Katedra Chorob Wewnetrznych, Pneumonologii i Alergologii Akademii Medycznej w Warszawie.

ECP released from the granules of activated eosinophils is regarded to be a marker of airway inflammation in asthma. The study was performed to compare the usefulness of measuring serum and sputum ECP for monitoring the asthma treatment. 29 subjects with mild to moderate asthma (mean age 41 +/- 17) were admitted in exacerbation (FEV1 55.54 +/- 87.49% N). 10 subjects with grass pollen asymptomatic asthma and 10 healthy subjects were also enrolled in the study. Patients with symptomatic asthma were ordered 30 mg prednisone for 2 weeks and they continued during next 2 weeks inhaled budesonide therapy. The concentrations of ECP (mcg/L) were determined by CAP-system (Pharmacia). The total eosinophil count and serum ECP in all subjects treated orally and next by inhaled GKS didn't differ statistically. The highest sputum ECP concentration was determined in exacerbation of asthma 84.5 +/- 78 mcg/L and statistically were reduced after 2-weeks of prednisone treatment 24.4 +/- 12.1 mcg/L (p = 0.05). In following 2 weeks of budesonide treatment sputum ECP concentration was statistically negligible in relation to previous treatment in spite of increasing tendency (50 +/- 61.3 mcg/L (p = 0.2394). In asymptomatic grass pollen asthma sputum ECP concentration was 19.7 +/- 9.4 mcg/L, higher than in controls 12 +/- 5.8 mcg/L (p = 0.04). There were a significant correlations between total eosinophil count and serum (r = 0.6396) and sputum ECP(r = 0.4683) in exacerbation. CONCLUSIONS: 1. In asthma exacerbation elevated sputum ECP concentration was observed. 2. In consequence of prednisone treatment the sputum ECP concentration was reduced. 3. Sputum ECP measurement is more accurate than serum ECP for monitoring the effectiveness of treatment. 4. Sputum ECP concentration is a sensitive parameter which discriminate asymptomatic patients with asthma from healthy subjects.

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Association between HLA-DQA1, -DQB1 gene polymorphisms and susceptibility to asthma in northern Chinese subjects.

Liu Y.

Department of Respiratory Disease, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China. jinming.gao TCH.harvard.edu

OBJECTIVE: Human leukocyte antigen (HLA) class II genes, especially HLA-DQ genes, which are highly polymorphic, have been thought to be candidate loci for the etiology of asthma, and shown to be involved in antigenic presentation. This study was conducted to investigate whether susceptibility or resistance to asthma is associated with HLA-DQA1 and DQB1 genes polymorphism. METHODS: Venous blood samples were collected from northern Chinese population with Han ethnic. (1) One hundred and twenty-five unrelated asthmatic individuals and 52 subjects from 12 asthmatic pedigrees. (2) Ninety-six healthy controls without asthma and atopy with the same ethnic. Genomic DNA was extracted using standard phenol-chloroform method. The second exon of HLA-DQA1 and DQB1 genes were amplified by sequence-specific primer-polymerase chain reaction (SSP-PCR) method. All asthmatics had their serum IgE (total and specific) antibody or skin-prick test measured, bronchial reactivity to methacholine (Mch) and bronchial reversibility by beta(2)-agonist evaluated. RESULTS: HLA-DQA1 * 0104 allele and HLA-DQB1 * 0201 allele were significantly higher in asthmatics than those in healthy controls (0.408 vs 0.177, P < 0.01; 0.568 vs 0.198, P < 0.01). Odds ratios (ORs) were 3.203 (95% CI 1.699 - 6.037), 5.328 (95% CI 2.883 - 9.849) respectively. Conversely, HLA-DQA1 * 0301 allele and HLA-DQB1 * 0301 were significantly decreased in asthmatics compared to healthy controls (0.296 vs 0.50, P < 0.01; 0.4 vs 0.563, P < 0.05); Logistic regression analysis showed that HLA-DQA1 * 0104 allele was associated independently with asthma etiology, OR [represented by Exp(B)] was 5.0942 with 95% CI 2.2520 - 21.1813; Spearman's analysis showed that HLA-DQA1 * 0104 allele and HLA-DQB1 * 0201 allele were positively associated with atopy, the correlation coefficient were 0.183 and 0.289 respectively, P < 0.01. By contrast, HLA-DQA1 * 0301 allele was negatively related to atopy, the correlation coefficient was -0.168, P < 0.05; linkage analysis did not support the view that HLA-DQA1/DQB1 genes were linked to asthma with LOD value being 0.72. CONCLUSIONS: HLA-DQA1 * 0104 allele and HLA-DQB1 * 0201 allele were implicated in susceptibility to asthma and atopy, HLA-DQA1 * 0301 allele and HLA-DQB1 * 0301 might be protective factor against asthma. Asthma and atopy are multifactorial disorders, HLA-DQA1 and DQB1 genes are involved in the regulation of immune specific response to common allergen.

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Indication of linkage and genetic heterogeneity for asthma and atopy on chromosomes 8p and 12q in 107 French EGEA families.

Demenais F.

INSERM U535, Villejuif, France. dizier vjf.inserm.fr

Using the sample of 107 families with at least two asthmatic siblings, as part of the EGEA study, we have investigated linkage to asthma (or atopy) and genetic heterogeneity according to the presence/absence of atopy (or asthma) using two approaches: (1) the triangle test statistic (TTS), which considers the identical by descent (IBD) distribution among affected sib-pairs discordant for another associated phenotype (eg asthmatic sib-pairs discordant for atopy) and (2) the predivided sample test (PST), which compares the IBD distribution of marker alleles between affected sib-pairs concordant and discordant for the associated phenotype. Two regions, 8p and 12q, already reported to be linked to both asthma and atopy, were examined here. A total of 20 asthmatic sib-pairs discordant for atopy and 24 atopic pairs discordant for asthma were analyzed by both TTS and PST methods and 83 pairs with atopic asthma by PST. Some evidence for linkage was observed for two markers in the 8p23.3-p23.2 region; D8S504 for asthma with genetic heterogeneity according to the presence/absence of atopy and D8S503 for atopy with genetic heterogeneity according to the presence/absence of asthma. In the 12q14.2-q21.33 region, there was also some evidence of linkage to two markers, D12S83 and D12S95, for atopy and asthma, respectively, with genetic heterogeneity according to the presence/absence of the associated trait. Provided the small distance between the two markers on either 8p (16 cM) or 12q (21 cM), it is unclear whether one or two genetic factors are involved in either region.

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Airway inflammation in childhood asthma.

Saetta M.

Divisione di Pneumologia, Dipartimento di Medicina Clinica e Sperimentale, Universita degli Studi di Padova, via Giustiniani 3, 35128 Padua, Italy. marina.saetta unipd.it

Airway pathology has been extensively investigated in adulthood asthma, whereas only few studies examined bronchial biopsies in childhood asthma. To evaluate the airway pathology in children with asthma, we analyzed bronchial biopsies obtained from 23 children undergoing bronchoscopy for clinical indications other than asthma. Nine had mild/moderate asthma. Six had atopy without asthma, and eight had no atopy or asthma. We measured basement membrane thickness and quantified the number of eosinophils, mast cells, neutrophils, macrophages, T lymphocytes, and positive cells for transforming growth factor-beta1 (TGF-beta1) and its receptors I and II (TGFbeta-RI and TGFbeta-RII) in subepithelium. Children with asthma had an increase in basement membrane thickness and in the number of eosinophils compared with control subjects, but not compared with children with atopy. They also had a decreased expression of TGFbeta-RII compared with both those with atopy and control subjects. In children with asthma, the number of eosinophils correlated negatively with TGFbeta-RII and positively with symptom duration. In conclusion, airway eosinophilia and basement membrane thickening, which are the pathologic features that are characteristic of adulthood asthma, are already present in children with mild asthma, and even in children with atopy without asthma. Moreover, in children with asthma but not in children with atopy without asthma, there is a downregulation of TGFbeta-RII.

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Mucosal and systemic inflammatory changes in allergic rhinitis and asthma: a comparison between upper and lower airways.

Prins JB.

Departments of Pulmonary Medicine and dagger Otorhinolaryngology, Erasmus University Medical Center Rotterdam, the Netherlands. gj.braunstahl wanadoo.nl

BACKGROUND: Local airway inflammation and airway remodelling are considered important in the clinical expression of allergic asthma. OBJECTIVE: The aim of this study was to compare airway inflammation and remodelling in nasal and bronchial mucosa of subjects with allergic rhinitis with or without asthma. METHODS: Four experimental groups were formed: allergic asthma and rhinitis (n = 19); allergic rhinitis, no asthma (n = 18); atopic subjects, no asthma, no rhinitis (n = 8) and non-allergic healthy control subjects (n = 16). Blood samples, nasal and bronchial biopsy specimens were collected during stable disease. Immunohistochemistry was performed for eosinophils (MBP), mast cells (CD117) and vascular endothelium (CD31). Epithelial loss, reticular basement membrane (RBM) thickness and subepithelial vascularity was assessed with a computer-assisted image analysis system. RESULTS: In nasal and bronchial mucosa, numbers of eosinophils were significantly higher in rhinitis patients with and without asthma than in asymptomatic atopics (P < 0.05) and controls (P < or = 0.01). In bronchial mucosa, the RBM was significantly thickened in rhinitis patients with and without asthma compared to asymptomatic atopics (P < 0.05) and controls (P < 0.01), while in nasal mucosa no differences were seen. Patients with asthma and rhinitis had increased numbers of blood eosinophils (P = 0.05) and skin test reactivity (P = 0.01) compared to patients with rhinitis only. No significant differences could be found between the investigated groups with respect to serum IL-5 and eotaxin levels, the number of mucosal mast cells and the degree of epithelial loss and subepithelial vascularity. Epithelial desquamation was significantly increased in the bronchial mucosa compared to nasal mucosa, not only in asthmatics (P < 0.001), but also in atopics without asthma and rhinitis (P = 0.02). CONCLUSIONS: This study shows that allergic inflammation, increased basement membrane thickness and epithelial desquamation are present in the lower airways of atopic subjects, even before the onset of clinical symptoms. Despite the presence of inflammatory cells, no structural changes could be assessed in nasal mucosa of allergic patients.

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

Bardin PG.

Respiratory Cell & Molecular Biology Research Division, University of Southampton, Southampton, UK.

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.

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PAR-2 activation, PGE2, and COX-2 in human asthmatic and nonasthmatic airway smooth muscle cells.

Burgess JK.

Dept. of Pharmacology, Univ. of Sydney, New South Wales 2006, Australia.

The protease-activated receptor-2 (PAR-2) is present on human airway smooth muscle (ASM) cells and can be activated by mast cell tryptase, trypsin, or an activating peptide (AP). Trypsin induced significant increases in PGE2 release from human ASM cells after 6 and 24 h and also induced cyclooxygenase (COX)-2 mRNA expression and COX-2 protein. Tryptase and the PAR-2 AP did not alter PGE2 release or COX-2 protein levels, suggesting a lack of PAR-2 involvement. When we compared results in asthmatic and nonasthmatic muscle cells, both trypsin and bradykinin induced less PGE2 from asthmatic ASM cells, and bradykinin induced significantly less COX-2 mRNA in asthmatic cells. Significantly less PGE2 was released from proliferating ASM cells from asthmatic patients. In conclusion, trypsin induces PGE2 release and COX-2 in human ASM cells, which is unlikely to be via PAR-2 activation. In addition, ASM cells from asthmatic patients produce significantly less PGE2 and COX-2 compared with nonasthmatic cells. These findings may contribute to the increase in muscle mass evident in asthmatic airways.

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