Biomedical subjects
H Magnussen
Publications and source records attributed to H Magnussen.
Effect of proinflammatory cytokines on interleukin-8 mRNA expression and protein production by isolated human alveolar epithelial cells type II in primary culture.
Alveolar epithelial cells type II (AEC-II) are ideally situated to regulate the recruitment and activation of different types of cells through the production of chemokines in response to inflammatory stimulation from the alveolar space. We hypothesized that these cells are important producers of interleukin-8 (IL-8) in the lung. This lead us to investigate the capacity of isolated human AEC-II cells to release IL-8 and whether this IL-8 release is regulated by proinflammatory cytokines, i.e. IL-1 beta, TNF-alpha and IFN-gamma. We isolated AEC-II from tumor-free sections of human lungs obtained by pneumectomy and purified the cells by magnetic activated cell sorting. For control experiments the AEC-II-like cell line A549 was used. IL-8 concentration was measured by ELISA in supernatants of unstimulated and LPS-, IL-1 beta-, TNF-alpha- and IFN-gamma- stimulated cells. IL-8 mRNA expression was evaluated by RT-PCR. Spontaneous IL-8 mRNA expression and protein secretion by AEC-II were significantly higher in comparison with A549 cells. TNF-alpha increased both IL-8 mRNA expression and protein production, whereas IL-1 beta slightly increased IL-8 release but did not change mRNA expression in AEC-II. LPS and IFN-gamma did not influence IL-8 expression in AEC-II and A549 cells. These results show considerable differences between A549 cell and AEC-II. The latter are capable of producing IL-8 under the control of proinflammatory cytokines. Our findings demonstrate that the modulation of IL-8 release in AEC-II may have an important impact on the immunoreactivity of these cells during pulmonary inflammation in vivo.
[Diagnostics in bronchial asthma].
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Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma. European Respiratory Society.
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Passive sensitization of human airways increases responsiveness to leukotriene C4.
Passive sensitization of human airways in vitro causes increased responsiveness to histamine and induces specific immunoglobulin (Ig)E-dependent contractile responsiveness to allergen. Leukotrienes (LTs) and, to a lesser extent, histamine are the major mediators of allergen-induced contraction. Since it is unclear whether passively sensitized airways are also hyperresponsive to cysteinyl leukotrienes, this study investigated the effect of passive sensitization on LTC4-, in addition to histamine- and allergen-induced contractions in vitro. Bronchial rings from nine nonatopic patients were sensitized overnight with serum containing high levels of total IgE (>250 U x mL(-1)) and allergen-specific IgE against Dermatophagoides farinae (fluorescence allergosorbent test) (FAST class > or =3). The potency (-log10 of the mediator concentration causing a half maximal response (pEC50) of histamine was significantly increased in serum-sensitized tissues compared to nonsensitized controls ((mean+/-SEM) pEC50 5.20+/-0.27 versus 5.64+/-0.18; p=0.02) and maximal contractions were enhanced (877+/-47 versus 543+/-51 mg; p<0.0001). Similarly, the potency of LTC4 was significantly increased in sensitized compared to nonsensitized bronchial rings (pEC50 9.37+/-0.20 versus 8.66+/-0.26; p=0.004); maximal contractions were also enhanced (811+/-57 versus 361+/-86 mg; p<0.0001). These data demonstrate that passive sensitization of human airways induces an increase not only in histamine but also in leukotriene responsiveness. Therefore, it might be speculated that allergen responses in sensitized airways are effected through a combination of increased mediator release from inflammatory cells and increased responsiveness of airway smooth muscle.
Sequentially induced sputum in patients with asthma or chronic obstructive pulmonary disease.
It has been demonstrated that consecutive samples of induced sputum may differ with respect to cellular composition. The aim of this study was to compare two sequential sputum samples in patients with chronic obstructive pulmonary disease (COPD) and asthma with different severity. Two sputum inductions were performed 30 min apart and processed separately in healthy subjects (n=11), patients with moderate to severe COPD (n=10), asthmatics treated with beta2-agonists alone (group 1, n=11), inhaled steroids (group 2, n=12) or systemic steroids (group 3, n=7). In healthy subjects and asthma group 2, percentages of neutrophils decreased significantly between the two sputum inductions but did not change in COPD and asthma group 3. Percentages of eosinophils did not change significantly in any group of patients. Concentrations of interleukin (IL)-8 decreased significantly in the control group and asthma groups 1 and 2 but not in asthma group 3 and the COPD group. These data demonstrate differences in sputum composition between two consecutive samples which were most pronounced in healthy subjects. Therefore, pooling of sputum samples may affect the results, particularly in healthy subjects, in contrast to subjects with more severe asthma or chronic obstructive pulmonary disease. These findings may be suggestive of differences in the distribution of inflammation along the airways between distinct airway diseases.
Ozone-induced airway inflammatory changes differ between individuals and are reproducible.
To study whether the individual inflammatory response to ozone was reproducible, dose-dependent, and time-dependent, we performed two exposures to 250 ppb ozone, one to 125 ppb and one to filtered air, each for 3 h of intermittent exercise and separated by at least 1 wk. Twenty-one healthy and 15 asthmatic subjects participated in the study. One hour after the two exposures to 250 ppb ozone we observed a mean increase in sputum neutrophils of 17.9 and 17.9% in healthy and of 20.3 and 15.2% in asthmatic subjects (p < 0.05 each). Twenty-four hours after exposure, the respective values were 11.9 and 14.8%, and 9.1 and 16.1% (p < 0.05 each). In the whole group of subjects, individual changes in the percentage of neutrophils were significantly correlated between the two exposure days 1 h (r = 0.87, p < 0.001; intraclass correlation coefficient [Ri] = 0.86) as well as 24 h (r = 0.79, p < 0.001; Ri = 0.71) after exposure. The percentages of lymphocytes were increased 24 h after exposures (all subjects combined: p < 0.05). The decrease in FEV1 in both groups (p < 0.01), was also reproducible (r = 0.77, p < 0.001), but there were no correlations between changes in sputum parameters and lung function. Exposure to 125 ppb ozone caused a small increase (p < 0. 05) in the percentage of neutrophils in asthmatic subjects and in the concentrations of interleukin-8 in both groups combined. Our data demonstrate that inflammatory and lung function responses to ozone differ between individuals and are reproducible but not related to each other. Therefore, these responses appear to represent two independent factors underlying the airway response to ozone.
Monitoring airway inflammation in asthma by induced sputum.
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[Acceptance and long-term results of home mechanical ventilation in various thoracic diseases].
BACKGROUND: Home mechanical ventilation (HMV) is an important therapy for patients with respiratory insufficiency on the basis of neuromuscular diseases (NMD), chest wall deformities (CWD) and chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: We retrospectively analyzed the long-term results of all 144 patients (CWD = 47, COPD = 54, NMD = 43) who underwent a trial of non-invasive HMV from March 1990 to September 1997. RESULTS: Twenty-eight patients did not accept the HMV (19%), 7 with CWD (15%), 17 with COPD (32%) and 4 with NMD (9%). Thirty-nine of 113 patients, who accepted HMV, completed nasal ventilation for a minimum of 1 year. For all 3 groups the hypercapnia improved significantly (CWD 58 +/- 6 to 48 +/- 4 mm Hg, p < 0.001, COPD 61 +/- 7 to 46 +/- 6 mm Hg, p < 0.001, NMD 53 +/- 8 to 42 +/- 6 mm Hg, p < 0.001). CONCLUSION: HMV improves the hypercapnic ventilatory failure independent of the underlying disease. The rate of acceptance is lower in patients with COPD in comparison to CWD and NMD.
[Quality of life of various patient groups during home mechanical ventilation].
BACKGROUND: During home mechanical ventilation quality of life depends on improvement of ventilation and progress of the underlying disease. PATIENTS AND METHODS: Patients with chronic obstructive pulmonary disease (COPD; n = 11), neuromuscular diseases (NMD; n = 8) and scoliosis (n = 8) answered before and after 306 +/- 232 (64 to 910) days home mechanical ventilation a standardized and validated questionnaire (SF 36, Medical Outcomes Trust, Boston, USA). RESULTS: For all patients together physical functioning (16 +/- 22 to 24 +/- 26%), general health (33 +/- 15 to 41 +/- 20%) and vitality (25 +/- 16 to 45 +/- 22%) improved significantly (p < 0.05). For COPD vitality (22 +/- 15 to 46 +/- 22%), for patients with NMD mental health (62 +/- 9 to 70 +/- 10%) and for patients with scoliosis vitality (35 +/- 15 to 59 +/- 22%) and mental health (61 +/- 11 to 74 +/- 4%) improved. CONCLUSION: Home mechanical ventilation improves quality of life, but the improvement depends on the underlying disease.
[Spontaneous course of bilateral sarcoid granulomatosis].
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[Established combinations of inhaled corticoids and long-acting beta 2-symphathomimetics for long-term therapy of bronchial asthma. Position of an expert panel study].
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[Early rehabilitation of patients with COPD in the acute clinic].
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[Intermittent assisted ventilation in neuromuscular diseases: course and quality of life].
Intermittent non-invasive home ventilation is expected to improve the quality of life, but progression of underlying neuromuscular diseases may lead to a deterioration. We observed after 82-1085 days of such home mechanical ventilation (7 patients with muscular dystrophy (age [mean/std.) 33 +/- 15 years), 8 patients with amyotrophic lateral sclerosis (ALS. age 60 +/- 8 years) a nonsignificant decrease of vital capacity (1.6 +/- 0.4 rp. 1.2 +/- 0.4 l) and an improvement of hypercapnia (49.3 +/- 8.5 rp. 43 +/- 18.5 mmHg). Quality of life (SF-36, Medical Outcomes Trust, Boston, USA) increased significantly only for mental health in patients with ALS (55 +/- 13 rp. 64 +/- 17%). Despite progression of the underlying disease the quality of life remained stable under home mechanical ventilation and mental health improved.
[Use of home mechanical ventilation in patients with high grade chronic obstructive lung disease (COPD)].
UNLABELLED: Nasal intermittent positive pressure ventilation (NIPPV) ist well established in the treatment of chronic hypercapnic ventilatory failure in patients with scoliosis or neuromuscular diseases. It has been introduced in acute respiratory failure in patients with COPD. The role of NIPPV in the long term treatment in severe stable hypercapnic COPD patients has not been well established (Thorax 1996; 51: 455-7). PATIENTS AND METHODS: We analysed the results of blood gases and lung function in all stable chronic hypercapnic COPD patients (PaCO2 59 +/- 6 mmHg), who underwent a trial of NIPPV from 11/95 to 1/98 (n = 25; 12 f/13 m; mean age 62 +/- 10 years). Patients with acute respiratory failure or an additional obstructive sleep apnoea syndrome were excluded. NIPPV was performed over an individual hand-molded nasal mask in the assisted/controlled mode (4 volume-, 21 pressure-cycled). At the time of discharge (25 +/- 15 days after the initiation of NIPPV) patients were able to apply the ventilator during night for al least 6 h. At the time PaCO2 during NIPPV was 43 +/- 6 mmHg. RESULTS: 5 patients failed to continue NIPPV for long-term treatment, so it was discontinued after a period of 6 weeks. 20 patients (80%) continued NIPPV for 13 +/- 8 months (range 1-27 months), 2 patients died during NIPPV (after 1 and 13 months). NIPPV had no significant influence on lung function (FEV1 predicted 28 +/- 13 vs. 30 +/- 11%; intrathoracic lung volume 6.9 +/- 2.5 vs. 6.2 +/- 1.7 l) or respiratory muscle strength (Pimax 4.2 +/- 0.9 vs. 4.5 +/- 1.6 kPa). However, we observed a significant improvement in PaCO2 during spontaneous breathing (59 +/- 6 vs. 48 +/- 8 mmHg; p < 0.001) and in case of base excess (7.4 +/- 4.1 vs. 3.4 +/- 2.4 mmol/l; p < 0.003). CONCLUSION: NIPPV can improve hypercapnic ventilatory failure in a subgroup of severe stable COPD, provided patients are motivated and home mechanical ventilation is adequately performed.
[Asthma therapy in children and adults. Recommendations of the German Respiratory League of the German Society of Pneumology].
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Effects of a selective PDE4 inhibitor, D-22888, on human airways and eosinophils in vitro and late phase allergic pulmonary eosinophilia in guinea pigs.
The actions of a novel selective inhibitor of type 4 cyclic nucleotide phosphodiesterase (PDE4), D-22888, on human airway smooth muscle tone and human eosinophil respiratory burst in vitro and bronchoalveolar eosinophilia in allergen-challenged sensitized guinea pigs in vivo were assessed. D-22888 was a selective inhibitor of PDE4, exhibiting an IC50 against human neutrophil PDE4 of 0.15 microM, compared to IC 50 values of 4.4 microM and 1.1 microM for human platelet PDE3 and PDE5, respectively. D-22888 relaxed inherent tone in human bronchial rings in a concentration-dependent manner with an IC50 of 5.0 microM (geometric mean, 95% ci 3.0-8.4 microM) and also caused a concentration-dependent inhibition of opsonized zymosan-induced superoxide anion generation by human eosinophils with an IC50 of 3.1 microM (1.0-9.2 microM). Treatment of actively sensitized guinea pigs with single oral doses of D-22888 2 h before or 4 h after challenge reduced bronchoalveolar lavage (BAL) eosinophil numbers, 24 h after aerosol allergen challenge, by 48% and 73% at 10 mg/kg and 30 mg/kg, respectively, 2 h pre-challenge and 68% at 30 mg/kg 4 h post-challenge. Chronic twice-daily oral dosing with D-22888 for three days caused inhibition of 24 h post-challenge BAL eosinophilia, amounting to 88% at 30 mg/kg. These in vivo actions were comparable with those achieved with other selective PDE4 inhibitors and with the corticosteroid, dexamethasone. We conclude that D-22888 exerts actions on airway smooth muscle and eosinophil recruitment and activation that suggest that D-22888 may be a promising new drug for use in the treatment of allergic obstructive airways>> diseases such as bronchial asthma.
Cyclic nucleotide phosphodiesterase in human bronchial epithelial cells: characterization of isoenzymes and functional effects of PDE inhibitors.
Cyclic AMP (adenosine 3':5'-cyclic monophosphate, cAMP) is an intracellular second messenger that mediates the actions of endogenous hormones and neurotransmitters and also of drugs such as beta-adrenoceptor agonists. The presence of functional beta-adrenoceptors on human airway epithelial cells has been demonstrated but the expression of the cAMP-metabolizing enzyme, cyclic nucleotide phosphodiesterase (PDE) in these cells has not been studied. We investigated the profile of activity of the different PDE isoenzymes in lysates of a pulmonary epithelial cell line, A549, and of human bronchial epithelial (HBE) cells grown in primary culture. The effects of non-selective and isoenzyme-selective PDE inhibitors on beta-agonist-induced elevations in intracellular cAMP concentrations and the production of interleukin (IL) 8 and prostaglandin (PG) E2 was also investigated. A549 cells expressed a high level of PDE4, lower levels of PDE1 and PDE3, and minor PDE5 activity. Primary HBE cultures expressed PDE4 and PDE1 activity at approximately equal levels with small additional PDE3 and PDE5 activities. The total PDE activity of the HBE cells was approximately nine-fold lower than that of A549 cells. The beta-adrenoceptor agonist salbutamol, caused a slow, concentration-dependent increase in intracellular cAMP levels in HBE cells which was not affected by a non-selective PDE inhibitor, IBMX (100 microM), or by a selective PDE4 inhibitor, rolipram (100 microM). Zardaverine, a dual-selective PDE3/PDE4 inhibitor, had no effect on cAMP levels at 10 microM but did cause a significant enhancement of salbutamol-induced elevations at 100 microM (150+/-36 pmol/10(5) cells at 10 microM salbutamol vs. 64+/-25 pmol/10(5) cells in the absence of zardaverine; n=3,P<0.01). Neither basal nor tumour necrosis factor alpha (10 ng/ml)-induced IL8 secretion was affected by salbutamol (10 microM) in the absence or presence of IBMX (100 microM). Salbutamol (10 microM), alone or in the presence of IBMX (100 microM) or rolipram (100 microM), also failed to affect basal or bradykinin (1 microM)-induced PGE2 release. Zardaverine (100 microM) caused a significant increase in basal PGE2 release but this was not enhanced in the presence of salbutamol (10 microM) and was not related to changes in cAMP levels. We conclude that HBE cells express a low total PDE activity, made up predominantly of PDE1 and PDE4 isoenzymes, and that intracellular cAMP levels in HBE cells are not related to the production of IL8 or PGE2.