Biomedical subjects

Axel Fischer

Publications and source records attributed to Axel Fischer.

At least 19 recordsLinked to original sources

PubMed2006

Analysis of airway secretions in a model of sulfur dioxide induced chronic obstructive pulmonary disease (COPD).

Hypersecretion and chronic phlegm are major symptoms of chronic obstructive pulmonary disease (COPD) but animal models of COPD with a defined functional hypersecretion have not been established so far. To identify an animal model of combined morphological signs of airway inflammation and functional hypersecretion, rats were continuously exposed to different levels of sulfur dioxide (SO2, 5 ppm, 10 ppm, 20 ppm, 40 ppm, 80 ppm) for 3 (short-term) or 20-25 (long-term) days. Histology revealed a dose-dependent increase in edema formation and inflammatory cell infiltration in short-term-exposed animals. The submucosal edema was replaced by fibrosis after long-term-exposure. The basal secretory activity was only significantly increased in the 20 ppm group. Also, stimulated secretion was significantly increased only after exposure to 20 ppm. BrdU-assays and AgNOR-analysis demonstrated cellular metaplasia and glandular hypertrophy rather than hyperplasia as the underlying morphological correlate of the hypersecretion. In summary, SO2-exposure can lead to characteristic airway remodeling and changes in mucus secretion in rats. As only long-term exposure to 20 ppm leads to a combination of hypersecretion and airway inflammation, only this mode of exposure should be used to mimic human COPD. Concentrations less or higher than 20 ppm or short term exposure do not induce the respiratory symptom of hypersecretion. The present model may be used to characterize the effects of new compounds on mucus secretion in the background of experimental COPD.

Journal Article↗

PubMed2006

Analysing the causes of chronic cough: relation to diesel exhaust, ozone, nitrogen oxides, sulphur oxides and other environmental factors.

Air pollution remains a leading cause of many respiratory diseases including chronic cough. Although episodes of incidental, dramatic air pollution are relatively rare, current levels of exposure of pollutants in industrialized and developing countries such as total articles, diesel exhaust particles and common cigarette smoke may be responsible for the development of chronic cough both in children and adults. The present study analyses the effects of common environmental factors as potential causes of chronic cough. Different PubMed-based researches were performed that related the term cough to various environmental factors. There is some evidence that chronic inhalation of diesel can lead to the development of cough. For long-term exposure to nitrogen dioxide (NO2), children were found to exhibit increased incidences of chronic cough and decreased lung function parameters. Although a number of studies did not show that outdoor pollution directly causes the development of asthma, they have demonstrated that high levels pollutants and their interaction with sunlight produce ozone (O3) and that repeated exposure to it can lead to chronic cough. In summary, next to the well-known air pollutants which also include particulate matter and sulphur dioxide, a number of other indoor and outdoor pollutants have been demonstrated to cause chronic cough and therefore, environmental factors have to be taken into account as potential initiators of both adult and pediatric chronic cough.

Journal Article↗

PubMed2006

Protease-activated receptor-2 activation exaggerates TRPV1-mediated cough in guinea pigs.

A lowered threshold to the cough response frequently accompanies chronic airway inflammatory conditions. However, the mechanism(s) that from chronic inflammation results in a lowered cough threshold is poorly understood. Irritant agents, including capsaicin, resiniferatoxin, and citric acid, elicit cough in humans and in experimental animals through the activation of the transient receptor potential vanilloid 1 (TRPV1). Protease-activated receptor-2 (PAR2) activation plays a role in inflammation and sensitizes TRPV1 in cultured sensory neurons by a PKC-dependent pathway. Here, we have investigated whether PAR2 activation exaggerates TRPV1-dependent cough in guinea pigs and whether protein kinases are involved in the PAR2-induced cough modulation. Aerosolized PAR2 agonists (PAR2-activating peptide and trypsin) did not produce any cough per se. However, they potentiated citric acid- and resiniferatoxin-induced cough, an effect that was completely prevented by the TRPV1 receptor antagonist capsazepine. In contrast, cough induced by hypertonic saline, a stimulus that provokes cough in a TRPV1-independent manner, was not modified by aerosolized PAR2 agonists. The PKC inhibitor GF-109203X, the PKA inhibitor H-89, and the cyclooxygenase inhibitor indomethacin did not affect cough induced by TRPV1 agonists, but abated the exaggeration of this response produced by PAR2 agonists. In conclusion, PAR2 stimulation exaggerates TRPV1-dependent cough by activation of diverse mechanism(s), including PKC, PKA, and prostanoid release. PAR2 activation, by sensitizing TRPV1 in primary sensory neurons, may play a role in the exaggerated cough observed in certain airways inflammatory diseases such as asthma and chronic obstructive pulmonary disease.

Animals↗

PubMed2006

Novel concepts of neuropeptide-based drug therapy: vasoactive intestinal polypeptide and its receptors.

Chronic inflammatory airway diseases such as bronchial asthma or chronic obstructive pulmonary disease (COPD) are major contributors to the global burden of disease. Although inflammatory cells play the central role in the pathogenesis of the diseases, recent observations indicate that also resident respiratory cells represent important targets for pulmonary drug development. Especially targeting airway neuromediators offers a possible mechanism by which respiratory diseases may be treated in the future. Among numerous peptide mediators such as tachykinins, calcitonin gene-related peptide, neurotrophins or opioids, vasoactive intestinal polypeptide (VIP) is one of the most abundant molecules found in the respiratory tract. In human airways, it influences many respiratory functions via the receptors VPAC1, VPAC2 and PAC1. VIP-expressing nerve fibers are present in the tracheobronchial smooth muscle layer, submucosal glands and in the walls of pulmonary and bronchial arteries and veins. Next to its strong bronchodilator effects, VIP potently relaxes pulmonary vessels, and plays a pivotal role in the mediation of immune mechanisms. A therapy utilizing the respiratory effects of VIP would offer potential benefits in the treatment of obstructive and inflammatory diseases and long acting VIP-based synthetic non-peptide compounds may represent a novel target for drug development.

Animals↗

PubMed2006

Chronic cough due to occupational factors.

Within the large variety of subtypes of chronic cough, either defined by their clinical or pathogenetic causes, occupational chronic cough may be regarded as one of the most preventable forms of the disease. Next to obstructive airway diseases such as asthma or chronic obstructive pulmonary disease, which are sometimes concomitant with chronic cough, this chronic airway disease gains importance in the field of occupational medicine since classic fiber-related occupational airway diseases will decrease in the future. Apart from acute accidents and incidental exposures which may lead to an acute form of cough, there are numerous sources for the development of chronic cough within the workplace. Over the last years, a large number of studies has focused on occupational causes of respiratory diseases and it has emerged that chronic cough is one of the most prevalent work-related airway diseases. Best-known examples of occupations related to the development of cough are coal miners, hard-rock miners, tunnel workers, or concrete manufacturing workers. As chronic cough is often based on a variety of non-occupational factors such as tobacco smoke, a distinct separation into either occupational or personally -evoked can be difficult. However, revealing the occupational contribution to chronic cough and to the symptom cough in general, which is the commonest cause for the consultation of a physician, can significantly lead to a reduction of the socioeconomic burden of the disease.

Journal Article↗

PubMed2006

Tachykinins in the respiratory tract.

Tachykinins as substance P and neurokinin A belong to a family of peptides, which are released from airway nerves after noxious stimulation. They influence numerous respiratory functions under both normal and pathological conditions including the regulation of airway smooth muscle tone, vascular tone, mucus secretion and immune functions. For the most part the synthesis/release of tachykinins is associated with neuronal cells; nevertheless, inflammatory and immune cells can synthesize and release tachykinins under certain physiological conditions. Moreover, this second cellular source of tachykinins may play an important role in inflammatory airway diseases such as bronchial asthma or chronic obstructive pulmonary disease (COPD). Dual tachykinin (NK1 and NK2) receptor antagonists demonstrate a significant bronchoprotection and a possible future role in the development of novel therapeutic approaches. In addition, NK3 receptors could also possess a bronchoprotective action, however, their presence in the human respiratory tract still needs to be confirmed. The family of tachykinins has recently been extended by the discovery of a third tachykinin gene that encodes the previously unknown NK1 receptor selective tachykinins hemokinin 1, endokinin A and B. Together with other novel tachykinin peptides such as C14TKL-1 and virokinin further research is required to define their respiratory biological role in health and disease.

Animals↗

PubMed2006

Air conditioning systems as non-infectious health hazards inducing acute respiratory symptoms.

Chronic and acute exposure to toxic aerosols belongs to frequent causes of airway diseases. However, asthma attacks due to long-distance inhalative exposure to organic solvents, transmitted via an air condition system, have not been reported so far. The present case illustrates the possibility of air conditioning systems as non-infectious health hazards in occupational medicine. So far, only infectious diseases such as legionella pneumophila pneumonia have commonly been associated to air-conditioning exposures but physicians should be alert to the potential of transmission of toxic volatile substances via air conditioning systems. In view of the events of the 11th of September 2001 with a growing danger of large building terrorism which may even use air conditioning systems to transmit toxins, facility management security staff should be alerted to possible non-infectious toxic health hazards arising from air-conditioning systems.

Acute Disease↗

PubMed2005

Protease-activated receptor 2 expression in trigeminal neurons innervating the rat nasal mucosa.

Protease-activated receptor 2 (PAR2) is activated by trypsin and mast cell tryptase to induce widespread inflammation by unknown mechanisms. Trypsin and tryptase were shown to activate sensory neurons to release substance-P and related peptides to mediate neurogenic inflammation. In the present study, the expression of PAR2 and tachykinins were investigated in rat trigeminal neurons that were identified by retrograde labeling with rhodamine dye from the nasal mucosa by using neuronal tracing in combination with immunohistochemistry. We found that large subpopulation of all trigeminal neurons (43.5+/-2.6%) identified by the pan-neuronal marker PGP 9.5 were stained with PAR2-immunoreactivity. Of all trigeminal neurons, 7.5+/-2.1% were immunoreactive for tachykinins and PAR2, and only 3.9+/-1.7% of all trigeminal neurons expressed tachykinins, but not PAR2-immunoreactivity. The present study also found that a large number trigeminal neurons innervating the nasal mucosa expressed PAR2-immunoreactivity. Of the rhodamine-labeled trigeminal neurons, 52.5+/-1.8% were immunoreactive for only PAR2 expression, 7.3+/-1.9% contained tachykinins and PAR2, and 3.1+/-0.4 of the rhodamine-labeled trigeminal neurons were non-immunoreactive PAR2, but were positive for tachykinins-immunoreactivity. In conclusion, based on the co-localization of PAR2 and tachykinins in trigeminal sensory neurons innervating the nasal mucosa, the present study suggests that, following an activation of PAR2 receptor in tachykinergic neurons by trypsin and mast cell tryptase, there may be a triggering of tachykinin-mediated phenomena such as neurogenic inflammation in allergic or non-allergic rhinitis.

Animals↗

PubMed2005

Expression of substance P and nitric oxide synthase in vagal sensory neurons innervating the mouse airways.

INTRODUCTION: Airway sensory nerves have the capacity to release neuromediators such as substance P and nitric oxide to control airway functions. The aim of the present study was to investigate substance P and neuronal nitric oxide synthase (NOS-1) expression in airway-specific sensory neurons. METHODS: Airway-projecting neurons in the jugular-nodose ganglia were investigated for NOS-1 and substance P expression by neuronal tracing and double-labelling immunoreactivity. RESULTS: Of the Fast blue labelled neurons, 14.6+/-1.8% (mean+/-S.E.M.) were immunoreactive only for NOS-1, 3.0+/-0.3% for NOS-1 and substance P, 2.7+/-0.3% only for substance P, and 79.7+/-1.7% of the labelled neurons were nonimmunoreactive for substance P or NOS-1 but were partly positive for I-B4-lectin-binding. Fast blue labelled NOS and/or substance P-positive neurons were small to medium sized (<20 microm). CONCLUSION: Based on the expression of substance P and nitric oxide synthase in airway neurons, the present study suggests that there may be substance P and NO biosynthesis and release following a peripheral activation of the afferents, there could be a triggering of substance P and NO-mediated phenomena, including those related to airway inflammation, such as plasma extravasation and vasodilatation.

Amidines↗

PubMed2005

Dopamine type 2 receptor expression and function in rodent sensory neurons projecting to the airways.

Agonists of the dopamine receptors have been demonstrated to have bronchodilatory properties in pathologically constricted airways. The mechanism by which these agonists induce bronchodilatation is thought to involve airway sensory nerves. In this study, the expression and function of dopamine D(2) receptor were examined in sensory ganglia supplying the airways. Neuronal dopamine D(2) receptor mRNA expression was demonstrated by single-cell RT-PCR following laser-assisted microdissection. The projection of the neurons to the airways was confirmed by retrograde neuronal labeling. In functional studies, dopamine D(2) receptor agonists (AR-C65116AB and ropinirole) inhibited intraneuronal calcium mobilization in rat capsaicin-sensitive primary sensory neurons and capsaicin-induced plasma extravasation in the rat trachea. Our results provide support to the hypothesis that dopamine D(2) receptor activation inhibits neurogenic inflammation and proinflammatory reflex responses.

Airway Obstruction↗

PubMed2005

Substance P mediates AP-1 induction in A549 cells via reactive oxygen species.

A common feature in asthma is the induction of reactive oxygen species (ROS) and the AP-1 transcription factor during the inflammatory process. AP-1 induction leads to an increased expression of pro-inflammatory cytokines. Also, higher levels of the pro-inflammatory neuropeptide substance P (SP) have been reported in bronchoalveolar-lavage fluid of asthmatics. Here, the role of SP on ROS induction and the downstream activation of AP-1 in A549 airway epithelial cells was investigated by dichloroflourescein-diacetate method and reporter gene assays. The SP-mediated AP-1 induction was dependent on extracellular calcium and ROS. The likely source of ROS are the mitochondria as rotenone inhibited AP-1 induction and the p47phox subunit of the NADPH oxidase complex, responsible for ROS generation in phagocytotic cells, was not expressed in A549 cells assayed by RT-PCR. This is consistent with results obtained from cells of murine bronchial epithelium, isolated by laser capture microdissection. In summary, this study provides evidence for an SP-mediated induction of AP-1, which may contribute to the expression of pro-inflammatory cytokines.

Calcium↗

PubMed2005

Inflammatory cells as source of tachykinin-induced mucus secretion in chronic bronchitis.

Substance P and neurokinin A are regulatory peptides of the tachykinin family that influence many aspects of human airway function in health and diseases such as bronchial asthma or chronic obstructive pulmonary disease (COPD). Tachykinin-induced mucus secretion has been regarded as sensory nerve-dependent so far. We studied the distribution of tachykinin-mRNA and -peptide and its relation to NK-1 subtype-positive cells in human airway glands to assess if tachykinins may also be expressed in inflammatory cells. RT-PCR demonstrated the expression of tachykinin- and NK-1-mRNA in human airway tissues. In situ hybridisation resulted in preprotachykinin (PPT)-A mRNA-signal detection in inflammatory cells which were in close contact to myoepithelial cells of airway glands. NK-1 immunoreactivity was found in myoepithelial cells which were in direct contact to the PPT-A mRNA and tachykinin-positive cells. The present data directly demonstrate the presence of both PPT-A mRNA and tachykinin immunoreactivity in inflammatory airway cells which are in direct contact to NK-1 receptor positive glandular myoepithelium. Our findings indicate that besides neurally released tachykinins, also inflammatory cell-derived tachykinins may lead to glandular secretion via NK-1 receptor stimulation. This points to a major second source of these proinflammatory mediators in chronic inflammatory airway diseases such as COPD or asthma.

Bronchitis, Chronic↗

PubMed2005

Gene expression and regulation of nerve growth factor in atopic dermatitis mast cells and the human mast cell line-1.

The gene expression and regulation of nerve growth factor (NGF) in atopic dermatitis (AD) and the human mast cell line (HMC)-1 was investigated at the molecular level. NGF-stimulation of HMC-1 cells resulted in increases in tryptase activity and histamine contents, paralleled by an increase of tryptase and histamine at the transcriptional level. Also, an increased expression of NGF was found in AD lesions, in association with increased systemic NGF plasma levels. Further cutaneous sources for increased NGF levels were keratinocytes and fibroblasts. These findings demonstrate an increased expression of NGF in AD and effects on tryptase and histamine. Mast cells may be major mediators of neurotrophin effects in AD.

Cells, Cultured↗

PubMed2005

Biotic and abiotic transformations of methyl tertiary butyl ether (MTBE).

BACKGROUND: Methyl tertiary butyl ether (MTBE) is a fuel additive which is used all over the world. In recent years it has often been found in groundwater, mainly in the USA, but also in Europe. Although MTBE seems to be a minor toxic, it affects the taste and odour of water at concentrations of < 30 microg/L. Although MTBE is often a recalcitrant compound, it is known that many ethers can be degraded by abiotic means. The aim of this study was to examine biotic and abiotic transformations of MTBE with respect to the particular conditions of a contaminated site (former refinery) in Leuna, Germany. METHODS: Groundwater samples from wells of a contaminated site were used for aerobic and anaerobic degradation experiments. The abiotic degradation experiment (hydrolysis) was conducted employing an ion-exchange resin and MTBE solutions in distilled water. MTBE, tertiary butyl formate (TBF) and tertiary butyl alcohol (TBA) were measured by a gas chromatograph with flame ionisation detector (FID). Aldehydes and organic acids were respectively analysed by a gas chromatograph with electron capture detector (ECD) and high-performance ion chromatography (HPIC). RESULTS AND DISCUSSION: Under aerobic conditions, MTBE was degraded in laboratory experiments. Only 4 of a total of 30 anaerobic experiments exhibited degradation, and the process was very slow. In no cases were metabolites detected, but a few degradation products (TBF, TBA and formic acid) were found on the site, possibly due to the lower temperatures in groundwater. The abiotic degradation of MTBE with an ion-exchange resin as a catalyst at pH 3.5 was much faster than hydrolysis in diluted hydrochloric acid (pH 1.0). CONCLUSION: Although the aerobic degradation of MTBE in the environment seems to be possible, the specific conditions responsible are widely unknown. Successful aerobic degradation only seems to take place if there is a lack of other utilisable compounds. However, MTBE is often accompanied by other fuel compounds on contaminated sites and anaerobic conditions prevail. MTBE is often recalcitrant under anaerobic conditions, at least in the presence of other carbon sources. The abiotic hydrolysis of MTBE seems to be of secondary importance (on site), but it might be possible to enhance it with catalysts. RECOMMENDATION AND OUTLOOK: MTBE only seems to be recalcitrant under particular conditions. In some cases, the degradation of MTBE on contaminated sites could be supported by oxygen. Enhanced hydrolysis could also be an alternative.

Adsorption↗

PubMed2005

Neuronal plasticity in persistent perennial allergic rhinitis.

OBJECTIVE: Persistent perennial allergic rhinitis belongs to the most frequent diseases in occupational and environmental medicine. Because the innervation may play a role in the pathogenesis of the disease, the present study analyzed nasal mucosal nerve profiles. METHODS: Neuropeptide-containing nerve fibers were examined using immunohistochemistry and related to eosinophil and mast cell numbers. RESULTS: In contrast to constant numbers of mast cells, there was a significant increase in the number of eosinophils. Immunohistochemistry for calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and neuropeptide tyrosine (NPY) revealed abundant staining of mucosal nerves. Semiquantitative assessment of nerve fiber neuropeptide density demonstrated a significant increase of VIP-positive fibers in rhinitis tissues. CONCLUSIONS: The present data indicate a differential regulation of neuropeptide-containing nerve fibers with increased numbers of VIPergic fibers suggesting a modulatory role of the upper airway innervation in perennial allergic rhinitis.

Adolescent↗

PubMed2005

NOSIP and its interacting protein, eNOS, in the rat trachea and lung.

Endothelial nitric oxide synthase (eNOS), the major nitric oxide (NO)-generating enzyme of the vasculature, is regulated through multiple interactions with proteins, including caveolin-1, Hsp90, Ca2+-calmodulin, and the recently discovered eNOS-interacting protein, NOSIP. Previous studies indicate that NOSIP may contribute to the intricate regulation of eNOS activity and availability. Because eNOS has been shown to be abundantly expressed in the airways, we determined the expression and cellular localization of NOSIP in rat trachea and lung by RT-PCR and immunohistochemistry and examined the interaction of NOSIP with eNOS in lung by coimmunoprecipitation. In tracheal epithelium and lung, NOSIP mRNA expression was prevalent, as shown by RT-PCR, and the corresponding protein interacted with eNOS, as demonstrated by coimmunoprecipitation. Using immunohistochemistry, we found both NOSIP and eNOS immunoreactivity in ciliated epithelial cells of trachea and bronchi, while Clara cells showed immunoreactivity for NOSIP only. NOSIP and eNOS were present in vascular and bronchial smooth muscle cells of large arteries and airways, whereas endothelial cells, as well as bronchiolar and arteriolar smooth muscle cells, exclusively stained for NOSIP. Our results point to functional role(s) of NOSIP in the control of airway and vascular diameter, mucosal secretion, NO synthesis in ciliated epithelium, and, therefore, of mucociliary and bronchial function.

Amino Acid Sequence↗

PubMed2005

Transcriptional down-regulation of neurotrophin-3 in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) leads to progressive development of airflow limitation and is characterised by cough, mucus hypersecretion and inflammatory changes. These characteristic features of the disease may be modulated by neural mediators such as neurotrophins (NT). Here we examined the expression and transcriptional regulation of neurotrophins in bronchial biopsies of COPD patients and compared the data to control biopsies. Histology revealed characteristic changes in the COPD tissues, including remodelling of the epithelial lining. RT-PCR demonstrated the mRNA expression of neurotrophins in all biopsies. Immunohistochemistry confirmed the expression of different proteins. To assess changes in the transcriptional expression level, quantitative real-time PCR was carried out and revealed differential mRNA expression of neurotrophins, with marked down-regulation of NT-3 mRNA expression and constant levels of nerve growth factor (NGF), brain-derived nerve factor (BDNF), and NT-4/5 mRNA expression. The present data on neurotrophin-specific transcriptional down-regulation of NT-3 in human COPD indicate a pathophysiological role for neurotrophins in COPD.

Bronchi↗

PubMed2004

Substance P expression in TRPV1 and trkA-positive dorsal root ganglion neurons innervating the mouse lung.

In the present study, the co-localisation of substance P (SP) with the vanilloid receptor TRPV1 and the neurotrophin receptor tyrosine kinase trkA was analysed in airway-specific murine dorsal root ganglion (DRG) neurons. DRG neurons labelled with Fast Blue were predominantly found at the segmental levels T2-T5. Immunoreactivity for the receptor TRPV1 was localized to 12% of Fast Blue labelled DRG neurons. Double-labelling immunohistochemistry revealed that a substantial number of them also co-express SP (7.6 +/- 1.1% (mean +/- S.E.M.)), whereas neurons with immunoreactivity for TRPV1 only were found in 4.4 +/- 1.3% of the retrogradely labelled neuronal population. Further analysis of retrogradely labelled neurons showed that their majority expressed trkA (62.8 +/- 1.4%), neurofilament protein 68-kDa (64.8 +/- 1.5%) or glutamate alone (19.5 +/- 1.9%). SP was always expressed in trkA-positive neurons. Based on the extent of co-localization of SP with the receptors TRPV1 and trkA in DRG airway neurons, the present study indicates that the DRG pathway may have effects on the magnitude of neurogenic inflammation in airway diseases such as asthma.

Animals↗