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Biomedical subjects

H Magnussen

Publications and source records attributed to H Magnussen.

At least 181 records · Page 10Linked to original sources
PubMed1995

[Nicotine as therapy of obstructive sleep apnea?].

In 8 smokers (age 57 +/- 6 years, BMI 26.4 +/- 3.8 kg/m2) with an apnea-hypopnea index of 22.2 +/- 19.5 and who wanted to give up smoking with the help of nicotine plaster, various characteristic values of respiratory disturbances (among others, average and longest duration of various apnea and hypopnea, average and minimum oxygen saturation) were investigated during nicotine and control nights. All characteristic values, with the exception of the average oxygen saturation (from 93.7 to 94.4%, p < 0.02), did not change significant. These results indicate that nicotine could be an effective drug. However, it cannot yet be recommended for the treatment of obstructive sleep apnea because of some still unanswered questions (efficacy for non-smokers, side-effects, risk of addiction).

Administration, Cutaneous↗
PubMed1995

Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants.

In addition to its emerging immunodulatory properties, theophylline is a bronchodilator and also decreases mean pulmonary arterial pressure in vivo. The mechanism of action of this drug remains controversial; adenosine antagonism, phosphodiesterase (PDE) inhibition and other actions have been advanced to explain its effectiveness in asthma. Cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP) are involved in the regulation of smooth muscle tone, and the breakdown of these nucleotides is catalysed by multiple PDE isoenzymes. The PDE isoenzymes present in human bronchus and pulmonary artery have been identified, and the pharmacological actions of inhibitors of these enzymes have been investigated. Human bronchus and pulmonary arteries are relaxed by theophylline and by selective inhibitors of PDE III, while PDE IV inhibitors also relax precontracted bronchus and PDE V/I inhibitors relax pulmonary artery. There appears to be some synergy between inhibitors of PDE III and PDE IV in relaxing bronchus, and a pronounced synergy between PDE III and PDE V inhibitors in relaxing pulmonary artery. In neither tissue does 8-phenyltheophylline, a xanthine exhibiting adenosine antagonism but not PDE inhibition, cause any significant relaxation, implying that theophylline does not exert its actions through adenosine antagonism. The close correspondence of theophylline concentrations inhibiting bronchus or pulmonary artery PDE and those causing relaxation points towards PDE inhibition as the major mechanism of action of theophylline in smooth muscle relaxation.

Animals↗
PubMed1995

[Effects of the oxidizing agents ozone and nitrogen dioxide on the lung: studies of a cell culture model].

In experimental exposure studies with ozone or nitrogen dioxide a change in lung function and unspecific airway sensitivity was observed. These effects were paralleled by an induction of cellular and biochemical changes. The exposure of isolated cells in vitro led to a decrease in vitality, an increase in permeability and the secretion of mediators very similar to the composition found in bronchoalveolar lavage after in vivo exposure. The cell culture model, therefore, allows the study of the mechanism of these oxidative air pollutants and allows further the understanding of the influence of different cell types on the observed effects in vivo.

Cell Survival↗
PubMed1994

Cyclic nucleotide phosphodiesterases in the human lung.

Although theophylline has been used in the treatment of lung diseases, particularly bronchial asthma, since the nineteenth century, the mechanisms underlying its effectiveness remained poorly understood until quite recently. The identification of cyclic nucleotide phosphodiesterase (PDE)--the enzyme responsible for breaking down cyclic AMP and cyclic GMP within cells--as a target for methylxanthines such as theophylline led to a research effort that has resulted in the characterization of multiple forms of the PDE enzyme and the development of selective inhibitors for some of these forms. Using these drugs, it has been possible to identify the PDE "isoenzymes" in a number of tissues and cells and to demonstrate the functional effects of the inhibition of different PDEs upon these tissues. Studies on the smooth muscle of human airways and pulmonary arteries have identified isoenzyme-selective PDE inhibitors that are effective broncho- and vasorelaxants in vitro, and it is hoped that these agents may be effective in relieving airway obstruction and pulmonary hypertension in patients. In addition, selective inhibitors of certain PDE isoenzymes suppress the proinflammatory functions of a range of immune cells, including the lung mast cell and the alveolar macrophage. Selective inhibitors of PDE isoenzymes are beginning to undergo clinical trials for the treatment of asthma. The advancing understanding of the PDE distribution in the lung and the ever more precise characterization of distinct enzyme proteins should allow the development of site-selective drugs for the treatment of lung diseases, while minimizing the systemic side effects associated with nonselective PDE inhibitors such as theophylline.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors.

The effects of the nonselective phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the selective PDE inhibitors motapizone (type III), rolipram (type IV), zardaverine (type III/IV), and zaprinast (type V and I) on prostaglandin F2 alpha (PFG2 alpha)-induced tone in human pulmonary arteries was investigated. Relaxation was achieved by IBMX [concentration eliciting 50% of maximum response (EC50): 11.3 microM, n = 10], motapizone (EC50:3.0 microM, n = 7), zardaverine (EC50: 3.2 microM, n = 9), and zaprinast (EC50: 31.8 microM, n = 6), whereas rolipram was almost ineffective. The combination of motapizone and zaprinast (10 microM) was the most effective relaxant with supra-additive relaxation and a motapizone EC50 of 575 nM. Biochemical studies revealed the presence of the PDE isozymes I, III, IV and V in the cytosolic and particulate phases of arterial homogenates; PDE II was not detectable. Partial inhibition of adenosine 3',5'-cyclic monophosphate (cAMP)-hydrolyzing PDE activity was achieved with rolipram (26 +/- 2.2%) or motapizone (60 +/- 5.4%), whereas there was almost complete inhibition of total PDE activity with zardaverine (81 +/- 2.0%) or the combination of motapizone and rolipram (82 +/- 2.3%). Inhibition of guanosine 3',5'-cyclic monophosphate (cGMP)-hydrolyzing PDE activity was achieved with zaprinast (62 +/- 2.6%) and motapizone (13 +/- 2.3%), indicating the cGMP-hydrolyzing activity of PDE III. We conclude that four out of the five recognized PDE isozyme families are present in human pulmonary artery. PGF2 alpha-induced tone in this tissue is effectively relaxed through PDE inhibitors with selectivity for type III, III/IV, and type V PDE.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Passive sensitization of human bronchi augments smooth muscle shortening velocity and capacity.

We assessed whether incubation with human serum from atopic individuals containing high concentrations of immunoglobulin E (IgE) causes augmentation of maximal contraction of human bronchial smooth muscle from non-atopic subjects in vitro. Bronchi were obtained from eight patients undergoing lung resection, and force-velocity relationships were determined for eight pairs of epithelium-intact bronchial rings of generations 6-7 using an electromagnetic lever system, which allowed isotonic shortening when load-clamps [from 0 to maximal isometric force (P0)] were applied at specific times after onset of contraction. Contractions were elicited by supramaximal electrical field stimulation (50 Hz, 10 s train duration, 25 V). Optimal length (Lo) for each tissue was determined during equilibration. After resection, tissues were sensitized passively with human sera containing high titers (> 1,000 U/ml) of IgE by incubation for 16 h at 20 degrees C. Maximal shortening velocity (Vmax) was increased for passively sensitized bronchi [0.1150 +/- 0.0240 1/2 circumferences/s (1/2Cir/s)] compared with sham-sensitized bronchi [0.0731 +/- 0.0152 1/2Cir/s, P = 0.038]. Similarly, maximal shortening (delta Lmax) was augmented in sensitized bronchial rings (11.27 +/- 1.80 %Lo) compared with sham-sensitized tissues (8.19 +/- 1.39 %Lo, P = 0.012). However, P0 did not differ between sensitized (122.5 +/- 24.4 mN/cm2) compared with sham-sensitized tissues (138.4 +/- 32.1 mN/cm2, P = 0.642). Our data are the first demonstration that Vmax and delta Lmax are augmented in sensitized but not challenged human bronchial rings after passive sensitization using human serum containing high concentrations of IgE.

Bronchi↗
PubMed1994

Contraction of human bronchial smooth muscle caused by activated human eosinophils.

We assessed the effect of activated eosinophils isolated from human peripheral blood in causing contraction of explanted human bronchi in vitro. Sixty-three epithelium-intact fifth generation airway sections were obtained from 16 subjects undergoing lung resection for carcinoma. Eosinophils were isolated by negative immunoselection, and activation with 10(-7) M platelet-activating factor (PAF) was confirmed by measurements of eosinophil peroxidase (EPO) secretion and superoxide (O2-.) generation. EPO secretion increased from 68.6 +/- 13.4 ng/10(6) cells to 420 +/- 125 ng/10(6) cells after activation with PAF (P < 0.05). Similarly, PAF-induced O2-. generation increased from 15.3 +/- 4.64 nmol cytochrome c reduced/10(5) cells to 44.2 +/- 8.50 nmol cytochrome c reduced/10(5) cells (P < 0.05). Cells were instilled into an isolated airway pouch preparation, and, 60 min later, airway contractile responses were determined by optical micrometry as percent decrease in lumenal diameter (%decrease) and percent increase in wall thickness (%increase) using a calibrated magnifying lens. Treatment with either vehicle, PAF alone, or untreated eosinophils had no effect on airway caliber or thickness. PAF-activated cells caused a 30.5 +/- 1.52% decrease in airway caliber (P < 0.001 vs. untreated cells) and a 36.6 +/- 2.54% increase in wall thickness (P < 0.001 vs. untreated cells). Preincubation with A63162, a 5-lipoxygenase inhibitor, caused concentration-dependent inhibition of airway narrowing. After 10(-5) M A63162, decrease in airway diameter caused by PAF was 8.00 +/- 0.10% vs. 30.5 +/- 1.52% for PAF alone (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetamides↗
PubMed1994

Theophylline suppresses human alveolar macrophage respiratory burst through phosphodiesterase inhibition.

The effects of theophylline upon human alveolar macrophage function were assessed and compared with its action upon macrophage cyclic nucleotide phosphodiesterase (PDE) activity and cyclic adenosine monophosphate (cAMP) levels. In the concentration range of 10 mumol/liter to 1 mmol/liter, theophylline caused a concentration-dependent inhibition of opsonized zymosan-stimulated hydrogen peroxide (H2O2) generation and PDE-catalyzed cAMP hydrolysis and increased the cellular cAMP content. Macrophage H2O2 generation was also inhibited by forskolin, an activator of adenylyl cyclase, but whereas theophylline (1 mmol/liter) and forskolin (1 mumol/liter) exhibited a synergic elevation of macrophage cAMP, there was no synergy between the two agents in the inhibition of respiratory burst. The inhibition of H2O2 generation by theophylline was reversed by the competitive inhibitor of cAMP-dependent protein kinase, (Rp)8-bromoadenosine cyclic 3':5'-monophosphorothioate (Rp-8-Br-cAMPS; 100 mumol/liter), indicating that the functional effect of theophylline was mediated through the elevation of cAMP. The inhibition of H2O2 generation by theophylline was not affected by adenosine deaminase (0.1 U/ml), indicating that the inhibition did not involve adenosine antagonism. It is concluded that theophylline exerts a direct inhibitory action upon human alveolar macrophage function through the elevation of cAMP levels as a result of PDE inhibition, and that this effect is observed at concentrations of theophylline that may be achieved in serum during therapy.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Migration of human and guinea pig airway epithelial cells in response to calcitonin gene-related peptide.

Calcitonin gene-related peptide (CGRP) is contained within and secreted by nerves and neuroepithelial bodies in the airway epithelium. To determine whether CGRP is a chemoattractant, tracheal epithelial cells isolated from 23 guinea pigs, and bronchial epithelial cells isolated from seven human donors were grown in primary culture for 4 to 5 days. Cell migration was assessed in a blindwell chemotaxis chamber. A gelatin-coated polycarbonate filter (8-microns pore size) separated the upper wells containing 5 x 10(4) cells from the lower wells containing chemoattractant (either CGRP or insulin). Cells were stimulated for 6 h, after which migrated cells on the filter were stained and counted. Both insulin and CGRP elicited migration of guinea pig tracheal epithelial (GPTE) cells. Exposure to 30 micrograms/ml insulin caused migration of 26.5 +/- 4.0 cells versus 4.3 +/- 0.6 cells per 10 hpf for control (P < 0.001). Treatment with 10(-9) M CGRP elicited migration of 39.6 +/- 2.5 cells versus 2.6 +/- 0.9 cells per 10 hpf for control (P < 0.001). Human bronchial epithelial (HBE) cells also migrated after stimulation with either insulin or CGRP: after 10(-9) M CGRP, HBE cell migration was 41.0 +/- 6.1 cells versus 3.4 +/- 0.3 cells per 10 hpf (P < 0.002; n = 3). Checkerboard analysis showed that the migration to CGRP was both chemotactic and chemokinetic. Incubation with 10(-8) M hCGRP-(8-37), a receptor antagonist for CGRP, plus 10(-9) M CGRP decreased GPTE cell migration to 9.8 +/- 2.4 cells versus 38.6 +/- 1.2 cells per 10 hpf for 10(-9) M CGRP alone (P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The effect of oral N-acetylcysteine on lung glutathione levels in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by an increased oxidant burden and by a deficiency of glutathione, a major antioxidant, in the lung epithelial lining fluid (ELF). Therefore, a rational therapeutic approach is to reverse the imbalance between oxidants and antioxidants in the lung by enhancing the antioxidant screen. With this background, the aim of our study was to evaluate oral N-acetylcysteine (NAC) as a strategy to augment lung glutathione levels in patients with IPF. Concentrations of total glutathione in bronchoalveolar lavage fluid (BALF) were quantified spectrophotometrically, before and following oral therapy with 3 x 600 mg NAC per day for 5 days, in 17 nonsmoking patients with biopsy-proven IPF. The volume of ELF recovered by BAL was determined using the urea method. Pretherapy, total glutathione levels in ELF in IPF patients were significantly less than normal (187 +/- 36 vs 368 +/- 60 microM), in contrast to levels in BALF (0.99 +/- 0.12 vs 1.18 +/- 0.19 microM). Following therapy with oral NAC, glutathione levels in BALF were 1.54 +/- 0.24 microM (a significant increase compared to pretherapy), whereas the increase in ELF levels (319 +/- 92 microM) did not reach significance. The therapy was well-tolerated, and all routine clinical and bronchoscopic parameters remained unchanged. It is thus feasible and safe to augment deficient lung glutathione levels in patients with IPF; thereby, potentially augmenting pulmonary antioxidant protection.

Acetylcysteine↗
PubMed1994

Factor analysis of exercise capacity, dyspnoea ratings and lung function in patients with severe COPD.

In this study we aimed to determine the relationship between exercise capacity, clinical ratings of dyspnoea and lung function parameters in patients with severe chronic obstructive pulmonary disease (COPD) by means of the statistical method of factor analysis. Sixty two patients (mean age +/- SD, 66 +/- 9 yrs) in stable clinical condition, with a forced expiratory volume in one second (FEV1) < 65% of predicted were investigated. Before the study, therapy was optimized, including inhaled bronchodilators, theophylline and steroids. Exercise capacity was determined from the best 6 min walking distance achieved in five self-paced treadmill walks performed on consecutive days. Lung function testing comprised spirometry and body plethysmography. Four different tools were chosen to rate dyspnoea and quality of life: the Baseline Dyspnoea Index (BDI), the Oxygen Cost Diagram (OCD), a modified Medical Research Council (MRC) Scale, and the Chronic Respiratory Disease Questionnaire (CRQ). Principal component factor analysis revealed that the data could be reduced to three hypothetical underlying variables (factors), which accounted for 79% of the total variance. BDI, MRC, OCD, CRQ and walking distance were attributed to the first factor, forced expiratory volume in one second and airway resistance to the second factor, and lung volumes to the third factor. Thus, our data suggest that the pathophysiological condition of severe COPD is characterized by three statistically independent entities: 1) exercise capacity, dyspnoea and quality of life ratings; 2) airway obstruction; and 3) pulmonary hyperinflation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

[Experimental effects of air pollutants on healthy probands and asthmatic patients].

We investigated the acute airway response to nitrogen dioxide (NO2) and ozone in healthy and asthmatic subjects. A) 12 subjects with mild bronchial asthma and 8 healthy subjects were studied to determine the effects of shortterm exposure to NO2 on lung function, bronchoalveolar lavage cells and mediators, and bronchial mucosal biopsy specimens. The asthmatic subjects exhibited changes in prostanoid and leukotriene mediators but no changes in differential cell numbers after NO2 exposure, whereas the normal subjects showed no consistent effects. These results indicate that changes in mediator profile induced by NO2 may be found without concomitant alterations in differential cell numbers. B) Ozone has been demonstrated to induce deterioration of lung function and bronchial responsiveness but it is not clear whether subjects with asthma or rhinitis are more susceptible than normals. We studied the effect of a short-term exposure to ozone on lung function and airway responsiveness to methacholine in 12 subjects with atopic asthma, 18 subjects with allergic rhinitis, and 38 healthy subjects. There was a large interindividual variability in the airway response to ozone but no statistically significant difference between study groups with respect to changes of lung function and airway responsiveness. Our data indicate that an intrinsic variability in ozone sensitivity is of higher relevance than a pre-existing airway disease such as asthma or rhinitis. By comparing both studies we suggest that the relationship between airway disease and airway responsiveness to oxidant pollutants is not homogeneous over substances.

Adult↗