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Biomedical subjects

Claus Vogelmeier

Publications and source records attributed to Claus Vogelmeier.

At least 19 recordsLinked to original sources
PubMed2006

Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease.

RATIONALE: Exacerbations of chronic obstructive pulmonary disease (COPD) greatly contribute to declining health status and the progression of the disease, thereby incurring significant direct and indirect health care costs. The prevention of exacerbations, therefore, is an important treatment goal. OBJECTIVES: To assess the impact of combination therapy with salmeterol/fluticasone propionate compared with salmeterol alone on moderate and severe exacerbations in patients with severe COPD and a history of repeated exacerbations. METHODS: Randomized, double-blind, parallel-group study. After a 4-wk run-in period, 994 clinically stable patients were randomized to one of two treatment groups: 507 patients received the salmeterol/fluticasone combination 50/500 micro g twice daily and 487 received salmeterol 50 micro g twice daily for 44 wk. MAIN RESULTS: The total number of exacerbations was 334 in the combination therapy and 464 in the salmeterol group (p < 0.0001). The annualized rate of moderate and severe exacerbations per patient was 0.92 in the combination therapy and 1.4 in the salmeterol group, corresponding to a 35% decrease. In addition, the mean time to first exacerbation in the combination therapy group was significantly longer compared with that of the salmeterol group (128 vs. 93 d, p < 0.0001). Other endpoints, including health-related quality of life, peak expiratory flow, and use of rescue medication, were significantly improved in the combination therapy group. Both treatments were well tolerated. CONCLUSIONS: This study demonstrates that combination therapy with salmeterol/fluticasone compared with salmeterol monotherapy significantly reduces the frequency of moderate/severe exacerbations in patients with severe COPD.

Aged↗
PubMed2006

The anti-microbial peptide LL-37 inhibits the activation of dendritic cells by TLR ligands.

The endogenous anti-microbial peptide LL-37/hCAP-18 is an effector molecule of the innate host defense system at surfaces of the body. Besides its direct anti-microbial activity, the peptide interacts with different cell types. Dendritic cells (DCs) play a central role in mucosal host defense. It was the aim of the study to determine whether LL-37 modulates the response of DCs to pathogen-associated molecular patterns. Monocyte-derived DCs were stimulated with the Toll-like receptors (TLRs) ligands LPS, lipoteichoic acid and flagellin. We measured classical markers of DC maturation and assayed the ability of the DCs to activate T cell responses. Co-incubation with LL-37 resulted in suppressed activation of DCs. Levels of released IL-6, IL-12p70 and TNF-alpha and surface expression of HLA-DR, CD80, CD83, CD86 and the chemokine receptor CCR7 were decreased. Exposure of DCs to LL-37 during LPS exposure induced co-cultured naive T cells to produce less IL-2 and IFN-gamma and decreased their proliferation. The response of memory T cells to a recall antigen was also decreased. In conclusion, we demonstrate that the anti-microbial peptide LL-37 inhibits the activation of DCs by TLR ligands. We propose that LL-37 is a regulator of host defense responses at the intersection of innate and adaptive immune systems.

Amino Acid Sequence↗
PubMed2006

Allergic airway inflammation inhibits pulmonary antibacterial host defense.

The innate immune system of the lung is a multicomponent host defense system and in addition has an instructing role in regulating the quality and quantity of the adaptive immune response. When the interaction between innate and adaptive immunity is disturbed, pathological conditions such as asthma can develop. It was the aim of the study to investigate the effect of the allergic inflammation of the lung on the innate host defense during bacterial infection. Human bronchial epithelial cells were preincubated with Th2 cytokines and infected with Pseudomonas aeruginosa. The effect of the Th2 cytokines on the mRNA levels of antimicrobial peptides and the antimicrobial activity of HBEC was determined. To investigate the influence of an allergic inflammation on pulmonary host defense in vivo, mice sensitized and challenged with OVA were infected with P. aeruginosa, and the number of viable bacteria in the lungs was determined together with markers of inflammation like cytokines and antimicrobial peptides. Exposure of airway epithelial cells to Th2 cytokines resulted in a significantly decreased antimicrobial activity of the cells and in suppressed mRNA levels of the antimicrobial peptide human beta-defensin 2. Furthermore, mice with allergic airway inflammation had significantly more viable bacteria in their lungs after infection. This was consistent with reduced levels of proinflammatory cytokines and of the antimicrobial peptide cathelin-related antimicrobial peptide. These results show that an allergic airway inflammation suppresses the innate antimicrobial host defense. The adaptive immune system modulates the functions of the pulmonary innate immune system.

Allergens↗
PubMed2006

[Intermediate care units and noninvasive ventilation].

Intermediate care units (IMC) have been introduced to provide optimal patient management according to disease severity and to bridge the gap between intensive care (ICU) and general wards. Most patients that are referred to an IMC need monitoring and intensive analgetic treatment. Over the past years noninvasive ventilation (NIV) and weaning have emerged as important new forms of active treatment in the IMC. Most studies that have been published so far demonstrate that an IMC improves patient outcome and lowers costs, although randomized controlled trials are missing. NIV reduces mortality, the need for intubation as well as ICU and hospital length of stay in patients with chronic obstructive pulmonary disease (COPD) and other disorders that cause respiratory failure. In many cases NIV can be performed in the IMC, a fact that reduces the number of ICU admissions, lowers costs and improves patient care. The high prevalence of pulmonary diseases and NIV emphasizes the importance of pneumologists as directors of both ICU and IMC.

Analgesics↗
PubMed2006

Patient understanding, detection, and experience of COPD exacerbations: an observational, interview-based study.

STUDY OBJECTIVES: This study was conducted to gain insight into patients' comprehension, recognition, and experience of exacerbations of COPD, and to explore the patient burden associated with these events. DESIGN: A qualitative, multinational, cross-sectional, interview-based study. SETTING: Patients' homes. PATIENTS: Patients (n = 125) with predominantly moderate-to-very severe COPD (age > or = 50 years; with two or more exacerbations during the previous year). INTERVENTIONS: Patients underwent a 1-h face-to-face interview with a trained interviewer. MEASUREMENTS AND RESULTS: During the preceding year, patients experienced a mean +/- SD of 4.6 +/- 5.4 exacerbations, after which 19.2% (n = 24) believed they had not fully recovered. Although commonly used by physicians, only 1.6% (n = 2) of patients understood the term exacerbation, preferring to use simpler terms, such as chest infection (16.0%; n = 20) or crisis (16.0%; n = 20) instead. Approximately two thirds of patients stated that they were aware of when an exacerbation was imminent and, in most cases, patients recounted that symptoms were consistent from one exacerbation to another. Some patients (32.8%; n = 41), however, reported no recognizable warning signs. At the onset of an exacerbation, 32.8% of patients (n = 41) stated that they reacted by self-administering their medication. Some patients spontaneously mentioned a fear of dying (12.0%; n = 15) or suffocating (9.6%; n = 12) during exacerbations, and effects on activities, mood, and personal/family relationships were frequently reported. Physicians tended to underestimate the psychological impact of exacerbations compared with patient reports. CONCLUSIONS: This study shows that patients with frequent exacerbations have a poor understanding of the term exacerbation. Patient recollections suggest that exacerbation profiles vary enormously between patients but that symptoms/warning signs are fairly consistent within individuals, and are generally recognizable. Exacerbations appear to have a significant impact on patient well-being, including psychological well-being, and this may be underestimated by physicians.

Activities of Daily Living↗
PubMed2005

[Bronchodilators in chronic obstructive pulmonary disease (COPD)].

Bronchodilators form the foundation of the pharmacotherapy of patients with chronic obstructive pulmonary disease (COPD). Scores of information from numerous large-scale clinical trials, mechanistic differences between classes of bronchodilators, and anti-inflammatory/bronchodilator fixed combinations make the decision what compound primarily to prefer in COPD treatment a challenge. In this review of large, double-blind, clinical trials with anticholinergic drugs, long- and short-acting beta(2)-agonists, xanthines and different application forms and combination of these compounds will be examined for clinical efficacy. The following practical objectives were accepted to define effective disease management: improvement of lung function, physical parameters such as 6-min walking distance, reduction of exacerbation rate and severity, improvement of quality of life and dyspnea score. Based on this review, inhalation therapy with a long-acting bronchodilator such as tiotropium, formoterol or salmeterol is proposed for early treatment algorithm. The combination of an anticholinergic compound and a long-acting bronchodilator may have an additive effect on bronchodilatation. The addition of inhaled corticosteroids is only recommended in stages III and IV. Besides, pharmacotherapy of COPD should always be flanked by smoking prevention programs, and supportive therapy, if indicated in severe disease stages.

Adrenergic beta-Agonists↗
PubMed2005

Cell-specific modulation of surfactant proteins by ambroxol treatment.

Ambroxol [trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanole hydrochloride], a mucolytic agent, was postulated to provide surfactant stimulatory properties and was previously used to prevent surfactant deficiency. Currently, the underlying mechanisms are not exactly clear. Because surfactant homeostasis is regulated by surfactant-specific proteins (SP), we analyzed protein amount and mRNA expression in whole lung tissue, isolated type II pneumocytes and bronchoalveolar lavage of Sprague-Dawley rats treated with ambroxol i.p. (75 mg/kg body weight, twice a day [every 12 h]). The methods used included competitive polymerase chain reaction (RT-PCR), Northern blotting, Western immunoblotting, and immunohistochemistry. In isolated type II pneumocytes of ambroxol-treated animals, SP-C protein and mRNA content were increased, whereas SP-A, -B and -D protein, mRNA, and immunoreactivity remained unaffected. However, ambroxol treatment resulted in a significant increase of SP-B and in a decrease of SP-D in whole lung tissue with enhanced immunostaining for SP-B in Clara Cells. SP-A and SP-D were significantly decreased in BAL fluid of ambroxol-treated animals. The data suggest that surfactant protein expression is modulated in a cell-specific manner by ambroxol, as type II pneumocytes exhibited an increase in SP-C, whereas Clara cells exhibited an increase in the immunoreactivity for SP-B accounting for the increased SP-B content of whole lung tissue. The results indicate that ambroxol may exert its positive effects, observed in the treatment of diseases related to surfactant deficiency, via modulation of surfactant protein expression.

Ambroxol↗
PubMed2005

Nonrandom variability of respiration during sleep in healthy humans.

STUDY OBJECTIVES: Breath-to-breath variability is not purely random but is, instead, characterized by correlations on short- and long-term scales. Short-term correlations might reflect intact metabolic-control mechanisms. To investigate whether the higher variability of breathing during rapid eye movement (REM) compared to non-REM (NREM) sleep is of random or nonrandom nature--reflecting an altered respiratory control--short-term and long-term correlations of respiratory drive and timing were determined. DESIGN: A full-night polysomnogram with a pneumotachograph attached to a full-face mask was performed. For each breath during NREM and REM sleep, respiratory components were analyzed based on the quantitative airflow. SETTING: Data collection took place in the sleep laboratory. PARTICIPANTS: Twenty-nine healthy subjects (age, 25.8 +/- 3.1 years). MEASUREMENTS AND RESULTS: Long-term correlations are practically absent in respiratory timing and drive components during NREM sleep, whereas they are present during REM sleep. Short-term correlations are present in respiratory drive, tidal volume, and minute ventilation during both NREM and REM sleep. In all timing components, additional short-term correlations are absent. CONCLUSION: We conclude that from NREM to REM sleep, short-term regulation of respiratory drive remains strongly metabolically controlled and clearly different from the short-term regulation of the rhythm-generating function. Regulation of respiratory timing and drive during REM sleep is characterized by additional long-term correlations. We speculate that this is the result of cortical influences during phasic REM sleep. Thus, the variability of breathing during REM sleep contains a nonrandom component, such that breathing components remain dependent upon each other even with large time lags between components.

Adult↗
PubMed2005

TNF-alpha, TNF-beta, IL-6, and IL-10 polymorphisms in patients with lung cancer.

Apart from cigarette smoking, genetic factors seem to be of importance in the development of lung cancer. The present case-control study investigated frequencies of five inflammatory response gene polymorphisms (TNF-alpha-308, TNF-beta-Intron1-252, IL-6-174, IL-10-819 and IL-10-1082) in patients with lung cancer and controls. The study population consisted of 117 patients with lung cancer (77 patients with NSCLC, including 40 Squamous Cell Carcinoma and 26 Adenocarcinoma, and 40 patients with SCLC), 117 matched controls without pulmonary disease and 243 healthy individuals (population control). Genotype analyses revealed no difference in genotype frequencies using matched-pair analysis. However, in comparison to the population control, the IL-10-1082 genotypes carrying the G allele appeared with higher frequency in the SCLC group (p=0.006) [SCLC: 84.6%, population controls: 64.6%]. This yields an odds ratio of 3.01 for SCLC (95% CI = [1.21, 7.48]). No associations were seen for all other polymorphisms analysed. The study raises the possibility of a correlation between the IL-10-1082_G allele and the presence of SCLC in a German population. The functional IL-10-1082 polymorphism correlates with altered IL-10 levels and might influence lung cancer susceptibility by altered inflammatory responses in the airways.

Adenocarcinoma↗
PubMed2005

Economic assessment of adjustable maintenance treatment with budesonide/formoterol in a single inhaler versus fixed treatment in asthma.

OBJECTIVES: To compare the costs and effectiveness of adjustable maintenance dosing with budesonide/formoterol in a single inhaler versus fixed dosing in adults with asthma. METHODS: In this prospective, randomised, open-label, parallel-group, multicentre trial conducted in Germany, patients with asthma received budesonide/formoterol 160 microg/4.5 microg in a single inhaler (Symbicort Turbuhaler with two inhalations twice daily for a 4-week run-in period. Patients were then randomised to either adjustable maintenance dosing (one inhalation twice daily, stepping up to four inhalations twice daily for 1 week if asthma worsened; n=1679) or fixed dosing (two inhalations twice daily; n=1618) for 12 weeks. The primary efficacy variable was the change in health-related quality of life (HR-QOL), measured using the Asthma Quality of Life Questionnaire (standardised) during the randomised treatment period. Resource utilisation data were collected in parallel and combined with German unit costs to estimate direct and indirect costs (year 2001 values). RESULTS: Both treatment regimens were equally effective in maintaining HR-QOL and asthma control during the randomised treatment period. However, overall, patients in the adjustable maintenance dosing group took fewer daily inhalations of budesonide/formoterol than those in the fixed-dosing group (mean: 2.63 vs 3.82 inhalations; p<0.001). Adjustable maintenance dosing was associated with significantly lower asthma-related direct costs compared with fixed dosing (mean: 221 euro vs 292 euro; p<0.001). This pattern was maintained when patients were stratified into those with peak expiratory flow (PEF) of 60% to <80% predicted normal and those with PEF of>/=80% predicted normal and when total costs were considered. CONCLUSION: Adjustable maintenance dosing with budesonide/formoterol in a single inhaler maintained HR-QOL in adult patients with asthma at a significantly lower cost than fixed dosing.

Adolescent↗
PubMed2004

Inhibition of NF-kappaB mediated inflammation by siRNA expressed by recombinant adeno-associated virus.

NF-kappaB mediated inflammation is a key process to many diseases. RNA interference (RNAi) is the specific suppression of genes by short double-stranded RNA. It was the aim of the present study to modify NF-kappaBdependent inflammation by small interfering RNA (siRNA) expressed by recombinant adeno-associated virus (rAAV). To study the kinetics of rAAV mediated expression of siRNA, the expression of the luciferase gene was targeted and resulted in a significant decrease of luciferase activity as compared to a control vector in the human 293 cell line. The effect was dose dependent and was detectable 24 h after infection. rAAV coding for siRNA against the p65 subunit of NF-kappaBsignificantly reduced the p65 protein. In a cellular model of TNF-alpha induced inflammation, expression of siRNA against p65 significantly suppressed the secretion of IL-8 from BEAS-2B cells. In conclusion, rAAV vectors coding for siRNA are an useful tool for efficient gene silencing in mammalian cells and can be used to modify NF-kappaB mediated inflammation.

Cell Line↗
PubMed2004

Microbial DNA induces a host defense reaction of human respiratory epithelial cells.

Epithelial cells represent the initial site of bacterial colonization in the respiratory tract. TLR9 has been identified in B cells and CD 123(+) dendritic cells and found to be involved in the recognition of microbial DNA. It was the aim of the study to investigate the role of TLR9 in the host defense reactions of the respiratory epithelium. Respiratory epithelial cell lines (IHAEo(-), Calu-3) or fully differentiated primary human cells as air-liquid interface cultures were stimulated with bacterial DNA or synthetic oligonucleotides containing CpG motifs (CpG oligodeoxynucleotides). Expression of TLR9, cytokines, and human beta-defensin 2 was determined by quantitative RT-PCR or by ELISA. We found that TLR9 is expressed by respiratory epithelial cell lines and fully differentiated primary epithelial cells at low levels. Stimulation of the above-mentioned cells with bacterial DNA or CpG oligodeoxynucleotide resulted in an inflammatory reaction characterized by a dose-dependent up-regulation of cytokines (IL-6, IL-8) and human beta-defensin 2. Up-regulation of NF-kappaB in epithelial cells in response to the CpG motif containing DNA was inhibited by overexpression of a dominant negative form of MyD88. These results provide clear evidence that the human respiratory epithelium is capable of detecting microbial DNA by TLR9. The respiratory epithelium has an important function in triggering innate immune responses and therefore represents an interesting target for anti-inflammatory therapy.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Recombinant Sendai virus for efficient gene transfer to human airway epithelium.

Recombinant Sendai virus (rSeV) infects respiratory epithelial cells in animal models and cultures of undifferentiated human nasal cells. It was the aim of this study to investigate the capability of rSeV to express a transgene in human airway epithelium. Differentiated human airway epithelial cells were generated using air-liquid interface culture techniques. Application of rSeV coding for green fluorescence protein (GFP) onto the apical surface (using a multiplicity of infection of 3) resulted in expression of the transgene in more than 90% of the cells followed by decreasing numbers of positive cells during the observation time of 3 weeks. The infection of human respiratory epithelial cells is mediated by sialic acid residues at the apical surface. Despite the secretion of interleukin (IL)-8 and the replication of rSeV in the epithelial cells, the authors could not detect any cytopathic effect after the infection. In conclusion, rSeV infects differentiated human airway epithelial cells with high efficiency. Transgene expression is transient and accompanied by the secretion of an inflammatory cytokine.

Bronchi↗
PubMed2004

Peripheral arterial tonometry, oximetry and actigraphy for ambulatory recording of sleep apnea.

Autonomous nervous functions change with sleep stages and show characteristic changes associated with sleep disorders. Therefore, continuous monitoring of autonomous nervous functions during sleep can be used for diagnostic purposes. Recently, the peripheral arterial tonometry (PAT) has been introduced to determine peripheral arterial vascular tone on the finger being determined by sympathetic activity. We investigate a new ambulatory recording system which uses PAT, oximetry and actigraphy (Watch-PAT) in order to detect sleep apnea and arousal. The Watch-PAT is battery operated and attached to the wrist and has two finger sensors. Twenty-one patients with suspected sleep apnea were recorded with cardiorespiratory polysomnography and the new system in parallel. Seventeen recordings could be evaluated. The correlation for the apnea/hypopnea index derived from the sleep laboratory and the respiratory disturbance index derived from the Watch-PAT was r = 0.89 (p < 0.01) and between arousals and the respiratory disturbance index was r = 0.77 (p < 0.01). The correlation for the total sleep time compared between the two systems was r = 0.15 (n.s.). The Watch-PAT detects apneas and hypopneas with a reasonable reliability and it is very sensitive to arousals. The number of Watch-PAT events lies between the sum of apneas plus hypopneas and arousals. Arousals are not unique to apnea events and therefore the specifity of the Watch-PAT is limited. In conclusion, the Watch-PAT is well suited to perform therapy control studies in patients suffering from sleep apnea and being treated.

Adult↗