A polymorphism in ORMDL3 is associated not only with asthma without rhinitis but also with chronic obstructive pulmonary disease.

BACKGROUND: Asthma is a heterogeneous disease, and asthmatic patients without rhinitis more commonly have fixed airway obstruction, a feature that is also typical of chronic obstructive pulmonary disease (COPD). The Dutch hypothesis suggests that both COPD and asthma have common genetic risk factors. The purpose of this study was to assess the association between the polymorphism rs4795405 in the known asthma candidate gene ORMDL3 and asthma with and without rhinitis. We also analyzed COPD in order to investigate whether, in addition to a clinical overlap, there might also be a genetic overlap between COPD and asthma. METHODS: The population of this genetic association study comprised 493 Slovenian adults, distributed as follows: 131 patients with asthma (59 had asthma with rhinitis and 72 asthma without rhinitis), 59 patients with rhinitis only, 133 patients with COPD, and 170 controls. Genotypes for rs4795405 were determined using the TaqMan genotyping assay. RESULTS: rs4795405 was specifically associated with asthma without rhinitis. Assuming a recessive genetic model, we found the CC genotype in 26% of healthy controls, in 24% of patients with asthma with rhinitis (P = .862), and in 44% of patients with asthma without rhinitis (P = .006). Polymorphism rs4795405 was also associated with COPD, for which the CC genotype was found in 37% of cases (P = .045). CONCLUSIONS: rs4795405 was strongly associated with asthma without rhinitis, a subtype of asthma for which a higher degree of airway obstruction was found. These results show the importance of analyzing different asthma phenotypes in genetic association studies. We also observed a genetic overlap between COPD and asthma without rhinitis.

Airway angiogenesis in stable and exacerbated chronic obstructive pulmonary disease.

Angiogenesis is a prominent feature of structural tissue remodelling that occurs in chronic airway diseases, including chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the airway levels of VEGF, angiogenin, IL-8 and TNF-α in patients with COPD during the stable phase and during acute exacerbation of the disease. We analysed induced sputum samples from 28 patients with COPD. Thirteen of these patients were followed up and second samples of sputum were obtained during acute exacerbation of the disease. The two control groups consisted of 12 healthy smokers and seven healthy non-smokers, all with normal lung function tests. Concentrations of VEGF, angiogenin, IL-8, TNF-α and bFGF were measured by cytometric bead array. In the induced sputum of patients with stable COPD, concentrations of VEGF (P < 0.001, P = 0.02), angiogenin (P < 0.0001, P < 0.0001), IL-8 (P < 0.0001, P = 0.0021) and TNF-α (P < 0.001, P = 0.03) were significantly elevated in comparison with healthy smokers and non-smokers. No additional elevation of angiogenic factors was demonstrated at the time of exacerbation. There was a significant negative correlation between FEV1 and VEGF (P < 0.05, r = -0.38), angiogenin (P < 0.0001, r = -0.68) and IL-8 (P < 0.001, r = -0.54) among smokers (smoking COPD patients and healthy smokers). No significant differences were observed between groups of healthy smokers and non-smokers. These results showed increased airway angiogenesis in patients with COPD. Moreover, VEGF, IL-8 and angiogenin negatively correlated with pulmonary function, which suggests their important role in COPD airway remodelling. However, no additional angiogenic activation was found during exacerbation of COPD.

Airway angiogenesis in patients with rhinitis and controlled asthma.

BACKGROUND: Airway angiogenesis may be an important part of structural remodelling in the pathogenesis of asthma. The development of asthma is frequently preceded by rhinitis. OBJECTIVE: We sought to determine whether the levels of angiogenesis-related factors are elevated in airways of patients with rhinitis or controlled asthma. METHODS: We analysed the induced sputum of 18 rhinitis patients, 16 asthmatic patients, and 15 healthy controls. The concentrations of angiogenin, vascular endothelial growth factor (VEGF), IL-8, fibroblast growth factor (bFGF), and TNF-alpha were measured by cytometric bead arrays. RESULTS: We found significantly increased angiogenin and VEGF concentrations in the induced sputum supernatant of both rhinitis and asthma patients compared with that of the healthy control group (P< or =0.0005). With the exception of TNF-alpha, there was no difference in the other angiogenic factors; TNF-alpha levels were higher in the rhinitis group than in the control group (P=0.02). CONCLUSION: These in vivo results suggest increased airway angiogenesis in patients with rhinitis without asthma as well as in corticosteroid-treated and well-controlled asthma patients.

Serum cystatin C, a potent inhibitor of cysteine proteinases, is elevated in asthmatic patients.

The effect of asthma pathogenesis on serum cystatin C, a potent inhibitor of cysteine proteinases and a newly proposed marker of the renal function, has not been yet determined. The objectives were to determine the 24-h pattern of cystatin C and creatinine concentrations in sera of asthmatic patients in order to test whether their concentrations might reflect circadian rhythms, the disease severity and the effect of therapy. Serum concentrations of cystatin C and creatinine were determined in steroid-independent and steroid-dependent asthmatics before and after 1 week of treatment with methylprednisolone and cyclosporin A, respectively. Samples were collected every 4 h during a 24-h period. Little or no significant effects of time on cystatin C and creatinine concentrations over a 24-h period were observed in healthy and asthmatic sera. However, significantly higher cystatin C concentrations were found in asthmatic patients compared to controls which suggests its role in the pathogenesis of asthma. Methylprednisolone increased and cyclosporin A decreased serum cystatin C concentrations after 1 week of therapy. Additionally these results support the need for the evaluation of cystatin C as a marker of glomerular filtration rate determination in asthma.

Serum concentration and circadian profiles of cathepsins B, H and L, and their inhibitors, stefins A and B, in asthma.

BACKGROUND: In order to determine the effect of asthma on serum concentrations of cathepsins B, H and L, and stefins A and B, the circadian and concentration profiles were followed in steroid-independent and steroid-dependent asthmatics before and after 1-week treatment with methylprednisolone and cyclosporin A. METHODS: Serum samples were taken at 4-h intervals throughout a 24-h period. Cathepsin and stefin concentrations were assayed using specific ELISAs. Data were analysed by one-way ANOVA and least squares fit of 24-h cosine. RESULTS: Temporal analysis of these proteins revealed little or no significant changes with time over a 24-h period. In comparison to normal sera, cathepsin H concentrations were elevated in all asthmatic patients, concentrations of both stefins were decreased in steroid-independent asthmatics, and stefin A concentrations were increased in steroid-dependent asthmatics before therapy. The effect of methylprednisolone treatment was demonstrated on decreased cathepsin B and increased cathepsin L concentrations in post-therapy serum samples. On the other hand, cyclosporin A treatment led to increased concentrations of cathepsins H and L. However, concentrations of stefins A and B were unaffected. CONCLUSIONS: This study associated alterations in balance of serum cysteine proteinases and their inhibitors in asthmatic patients, which has raised the possibility of their involvement in asthma pathogenesis. Validated rhythms of cathepsins and stefins in asthmatic sera exhibited temporal differences, which are too small to influence the time of sampling for their quantitative measurement over the course of a day.

Flow cytometric analysis of lymphocytes isolated from nasal polyps.

We analyzed by flow cytometry the expression of IL-2 receptors (alpha subunit-CD25) and ICAM-1 adhesion molecules (CD54) on T cells and subsets (CD4, CD8) isolated from nasal polyp tissue in allergic and non-allergic patients. We found a significant increase in IL-2 receptor and ICAM-1 molecule expression on T cells isolated from nasal polyp tissue compared to peripheral blood lymphocytes. We also found a significantly increased expression of ICAM-1 molecules on CD8+ cells in non-allergic compared to allergic patients. The latter may reflect a difference in cytotoxic immune response between allergic and non-allergic patients, but the result should be confirmed in a more extensive study including cytokine and immunoglobulin analysis. We hope that it would enable us to obtain a deeper insight into the local immune events and further to clarify the etiology and pathogenesis of nasal polyps and their relation to allergy.

[Pharmacokinetics of Teolin 300 tablets and Teotard 350 capsules in asthma patients]. / Farmakokinetika tableta Teolin 300 i kapsula Teotard 350 u astmaticara.

Pharmacokinetics of tablets Teolin 300 (TT) and capsules Teotard 350 (TC) was studied in 7 asthma patients. Serum theophylline concentrations (SCT) were measured in 2-h intervals over 2 consecutive days for each theophylline formulation. A randomized, crossover design was used. In 12-h one dose of TT was absorbed 89.76 +/- 32.76% (means +/- SD) and TC 83.76 +/- 49.48%; between them there were statistically no differences. Amplitudes of SCT (AMP) were in the range 0.31 to 2.7 and mean 24-h SCT in the range 19.8 to 119.3 mumol/L. AMP were reproducible only to TT (r = 0.97, p less than 0.001). Fourier's harmonic analysis applied to mean SCT disclosed statistically significant 12-h oscillations only for TT (p less than 0.05). Continuous therapy with slow-release theophylline should always be monitored with measurements of SCT which should be interpreted by pharmacokinetics data of applied sustained theophylline formulation.

Anxiety and depression during hospital treatment of exacerbation of chronic obstructive pulmonary disease.

This study investigated the prevalence, risk factors and rate of recognition of anxiety and depression in 50 patients hospitalized for exacerbation of chronic obstructive pulmonary disease (COPD). Using the Primary Care Evaluation of Mental Disorders questionnaire, 13 patients were identified as having depression, four had anxiety and eight had a combination of the two. Patients with anxiety and/or depression had a significantly higher partial pressure of oxygen and pH, and a lower partial pressure of carbon dioxide, in arterial blood on admission, more severe dyspnoea after a 6-min walk test and less improvement of dyspnoea from admission to discharge than COPD patients without anxiety and/or depression. Two patients were referred to a mental health specialist during their hospitalization, indicating a low rate of recognition. The results suggest that patients with mental disorders are referred and admitted to hospital earlier in the course of a COPD exacerbation due to earlier and more intense perception of dyspnoea.