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Biomedical subjects

D A Groneberg

Publications and source records attributed to D A Groneberg.

At least 19 recordsLinked to original sources

[COPD--chronic obstructive pulmonary disease and its implications for the human organism].

Chronic obstructive pulmonary disease (COPD) belongs next to bronchial asthma to the most important diseases of the respiratory tract in terms of its socio-economic impact. Especially exacerbations of COPD and clinical end-stages exert extremely negative effects on the global burden of disease. This article analyses current aspects of COPD regarding epidemiology, pathogenesis, pathophysiology and diagnosis of the disease. Given the estimation that COPD will be the third most common cause of death in the year 2020, the high socio-economic costs and the primary cause tobacco smoke exposure, the disease can be regarded as extremely relevant for numerous aspects of insurance medicine.

Cost of Illness↗

[Pharmacotherapy of severe acute respiratory syndrome (SARS)].

Severe acute respiratory syndrome (SARS) constitutes the first new infectious disease of the current millennium. It is caused by the novel SARS-Coronavirus (SARS-CoV). SARS is related to a high morbidity and mortality and first appeared during an epidemic in 2002 - 2003. To date no specific therapy against the SARS-CoV is available. Due to the rapid spread of SARS during the epidemics in 2002 - 2003, randomised and controlled multicentre studies were not performed. Therefore, general guidelines have not been developed. Since the outbreak, scientists have been testing potential antiviral substances using in vitro and animal models. This study analyses the presently available in vitro and in vivo data on the pharmacotherapy of SARS.

Antiviral Agents↗

Airway hyper-responsiveness in allergic asthma in guinea-pigs is mediated by nerve growth factor via the induction of substance P: a potential role for trkA.

BACKGROUND: The neurotrophin nerve growth factor (NGF) has been implicated as a mediator in allergic asthma. Direct evidence that inhibition of NGF-induced activation of neurotrophin receptors leads to improvement of airway symptoms is lacking. We therefore studied the effects of inhibitors of NGF signal transduction on the development of airway hyper-responsiveness (AHR) and pulmonary inflammation in a guinea-pig model for allergic asthma. METHODS: Airway responsiveness to the contractile agonist histamine was measured in vivo in guinea-pigs that were sensitized and challenged with ovalbumin (OVA). Inflammatory cell influx and NGF levels were determined in bronchoalveolar lavage fluid (BALF). Substance P, a key mediator of inflammation, was measured in lung tissue by radioimmunoassay, while substance P immunoreactive neurons in nodose ganglia were measured by immunohistochemistry. RESULTS: OVA challenge induced an AHR after 24 h in OVA-sensitized guinea-pigs. This coincided with an increase in the amount of NGF in BALF. Simultaneously, an increase in the percentage of substance P immunoreactive neurons in the nodose ganglia and an increase in the amount of substance P in lung tissue were found. We used tyrosine kinase inhibitors to block the signal transduction of the high-affinity NGF receptor, tyrosine kinase A (trkA). Treatment with the tyrosine kinase inhibitors (K252a or tyrphostin AG879) both inhibited the development of AHR, and prevented the increase in substance P in the nodose ganglia and lung tissue completely whereas both inhibitors had no effect on baseline airway resistance. Neither treatment with K252a or tyrphostin AG879 changed the influx of inflammatory cells in the BALF due to allergen challenge. CONCLUSIONS: We conclude that substance P plays a role in the induction of AHR in our model for allergic asthma which is most likely mediated by NGF. As both tyrosine kinase inhibitors AG879 and K252a show a similar inhibitory effect on airway function after allergen challenge, although both tyrosine kinase inhibitors exhibit different non-specific inhibitory effects on targets other than trkA tyrosine kinases, it is likely that the induction of substance P derived from sensory nerves is mediated by NGF via its high-affinity receptor trkA.

Animals↗

Amelioration of anemia after kidney transplantation in severe secondary oxalosis.

INTRODUCTION: In small bowel disease such as M. Crohn, the intestinal absorption of oxalate is increased. Severe calcium oxalate deposition in multiple organs as consequence of enteric hyperoxaluria may lead to severe organ dysfunction and chronic renal failure. The management of hemodialyzed patients with short bowel syndrome may be associated with vascular access problems and oxalate infiltration of the bone marrow leading to pancytopenia. Although the risk of recurrence of the disease is very high after renal transplantation, it may be the ultimate therapeutic alternative in secondary hyperoxaluria. CASE: Here, we report a patient with enteric oxalosis due to Crohn's disease. He developed end-stage renal disease, erythropoietin-resistant anemia, oxalate infiltration of the bone marrow and severe vascular access problems. Following high-urgency kidney transplantation, daily hemodiafiltration of 3 hours was performed for 2 weeks to increase oxalate clearance. Despite tubular and interstitial deposition of oxalate in the renal transplant, the patient did not require further hemodialysis and the hematocrit levels normalized. DISCUSSION: Early treatment of hyperoxaluria due to short bowel syndrome is essential to prevent renal impairment. Declining renal function leads to a further increase in oxalate accumulation and consecutive oxalate deposition in the bone marrow or in the vascular wall. If alternative treatments such as special diet or daily hemodialysis are insufficient, kidney transplantation may be a therapeutic alternative in severe cases of enteric oxalosis despite a possible recurrence of the disease.

Adult↗

[Drug transport in the respiratory epithelium].

The aerosolic administration of peptidomimetic drugs with a peptide backbone may play a crucial role in the future treatment of diseases. Especially rational drug design offers an option to synthesize new drugs that are carried by specific drug transporters. Out of the presently identified transporter proteins PEPT1 and PEPT2, the high-affinity transporter PEPT2 is found in the respiratory tract. The transporter possess 12 membrane spanning domains and catalyses an electrogenic uphill drug transport using a transmembrane electrochemical proton gradient. PEPT2 is expressed in the bronchial epithelium and in alveolar type II pneumocytes in human airways. Kinetic studies demonstrated that peptidomimetic compounds including antibiotic, antiviral and antineoplastic drugs are carried by PEPT2. The transporter also carries delta-aminolevulinic acid into the airways. This molecule can be used for the diagnostics of pulmonary neoplasms and for photodynamic therapy. Using the recently published data on minimal structural requirements for PEPT2-substrates, rational drug design may lead to a new generation of respiratory drugs and prodrugs, which are delivered to the airways via the molecular mechanisms of the PEPT2 transport system.

Aerosols↗

[Air quality and particulate matter].

Clean air is considered to be a key factor influencing human health. It is not only important for respiratory health but influences the homeostasis of the whole human organism. In this respect, all major national and international respiratory societies point to the extremely important role of national and international clean air acts that address both inner (i. e. tobacco smoke) and outer (i. e. environmental pollutants) air pollution. Due to research at the levels of pulmonary medicine and environmental medicine, the European Union has implemented new limit values. Clinical and experimental evidence points out that it is crucial to comply with these regulations since recent studies have shown that not only patients with lung diseases but also children and their lung development are endangered by high concentrations of air pollutants. With regard to the complexity of detrimental effects new national and international research programs should be established for the assessment of health effects of air pollutants.

Air↗

Allergic airway inflammation induces tachykinin peptides expression in vagal sensory neurons innervating mouse airways.

BACKGROUND: Allergic airway inflammation has been shown to induce pro-inflammatory neuropeptides such as tachykinin peptides substance P (SP) and neurokinin A (NKA) together with related peptide like calcitonin gene-related peptide (CGRP) in nodose sensory neurons innervating guinea-pig airways. OBJECTIVE: The present study was designed to examine the effects of allergen sensitization and challenge on the SP/NKA expression in the jugular-nodose ganglion neurons innervating the murine airways. METHODS: Using retrograde neuronal tracing technique in combination with double-labelling immunohistochemistry, the expression of SP/NKA was investigated in a murine model of allergic airway inflammation. RESULTS: Allergic airway inflammation was found to induce the expression of SP/NKA (13.2+/-1.43% vs. 5.8+/-0.37%, P<0.01) in large-diameter (>20 microm) vagal sensory neurons retrograde labelled with Fast blue dye from the main stem bronchi. CONCLUSION: Based on the induction of tachykinins in airway-specific large-sized jugular-nodose ganglia neurons by allergic airway inflammation, the present study suggests that allergen sensitization and challenge may lead to de novo induction of tachykinins in neurons. This may partly contribute to the pathogenesis of airways diseases such as allergic airway inflammation.

Allergens↗

Mast cells and vasculature in atopic dermatitis--potential stimulus of neoangiogenesis.

BACKGROUND: Atopic dermatitis skin lesions are characterized by inflammatory changes and epithelial hyperplasia requiring angiogenesis. As mast cells may participate in this process via bidirectional secretion of tissue-damaging enzymes and pro-angiogenic factors, the present study aimed to assess the occurrence and possible function of mast cells in the papillary dermis and in epidermal layers of atopic dermatitis lesions. METHODS: Semi-thin and serial sections in combination with immunohistochemistry, histochemistry and proliferating cell nuclear antigen (PCNA)-activity assays were used and related to epidermal thickness and targeted gene expression studies. RESULTS: Mast cells were located in the papillary dermis and migrated through the basal lamina into the epidermis of atopic dermatitis lesions. An increased PCNA-activity in cells of superficial epidermal layers indicated an activation of keratinocytes and stimulation of endothelial growth. Only approximately 30% of the papillary mast cells stained with the tryptase were toluidin-blue-positive, and approximately 80% were chymase positive. A high number of mast cells expressed c-kit. Most papillary and epidermal mast cells were localized close to endothelial cells. Vascular expression of endoglin (CD105) demonstrated neoangiogenic processes. Mast cells stimulation led to the expression of proangiogenic factors. Also, gene expression of tissue-damaging factors such as matrix metalloproteinases was increased. CONCLUSIONS: These data suggest that in atopic dermatitis, mast cells are abundantly localized close to and within the epidermis where they may stimulate neoangiogenesis. Via the new vessels, inflammatory cells, together with complement components and antibodies, can be transported to the epidermis to aid in the defense against environmental antigens and to maintain chronic inflammation.

Blood Vessels↗

Gene expression and regulation of transcription factor activator protein-2 alpha in human mast cells.

BACKGROUND: The transcription factor activator protein (AP)-2 regulates cell-type specific gene expression during development and differentiation, but its role in mast cell development has so far not been explored. METHODS: Gene expression and regulation of AP2 was assessed in normal skin, diseases with increased mast cell numbers, and in vitro models of mast cell differentiation. RESULTS: AP-2alpha-protein was not detectable in normal skin but in mastocytoma lesional mast cells. AP-2alpha-mRNA and -protein were also detected in leukemic mast cells (HMC-1), in the adherent fraction of peripheral blood (PBMC) and umbilical cord blood mononuclear cells (CBMC), and AP-2alpha-mRNA at low levels in isolated-purified mast cells. During culture with fibroblast supernatants or SCF, AP-2alpha-mRNA was de novo expressed in KU812-cells, maintained at about the same level in PBMC and CBMC, and upregulated in HMC-1-cells. On extended culture, a down-regulation was noted at mRNA and/or protein levels. In contrast, tryptase expression increased in all cells throughout culture, as did c-Kit in normal cells, whereas in both leukemic cell lines, c-Kit was maintained unchanged at about the same level. CONCLUSIONS: These findings suggest a continuous activation of AP-2alpha in mastocytomas and mast cell leukemia and its transient upregulation during c-Kit dependent early steps of normal mast cell differentiation.

Cell Line↗

[Vasoactive intestinal polypeptide in the respiratory tract: physiology and pathophysiology].

Peptidergic neuromediators have gained importance in the field of respiratory physiology and pathophysiology due to the characterisation of numerous pulmonary effects in the past years. With regard to the multitude of mediators, the neuropeptide vasoactive intestinale polypeptide (VIP) plays a special role as it exerts potent anti-inflammatory and immunomodulatory effects. Neurophysiologically the peptide has been attributed to the family of the inhibitory non-adrenergic non-cholinergic (i-NANC) neuromediators of the pulmonary innervation. VIP-containing nerve fibres are localized in the airway and vascular smooth muscle layers of trachea and bronchi in the human respiratory tract. Apart from strong vasodilatory effects, the peptide also shows a high bronchodilatory potency. In a large number of respiratory diseases VIP may play a pathophysiological role. In this respect, increased levels of VIP have been demonstrated for inflammatory diseases of the upper and lower airways and the peptide may also play a role in pulmonary hypertension. Due to its fast enzymatic cleavage, VIP-based therapies have not been used in routine therapy so far. Also, the use of synthetic VIP-agonists did not lead to an improved outcome in patients with bronchial asthma if compared to classical drugs. However, recent data from animal experiments indicate potent immunomodulatory effects which suggest a future use of this mediator and its agonists in the therapy of immune diseases.

Anti-Inflammatory Agents↗

Phenotypic alteration of neuropeptide-containing nerve fibres in seasonal intermittent allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is the most common allergic disease affecting the respiratory tract. Next to inflammatory changes, the airway innervation plays an important modulatory role in the pathogenesis of the disease. OBJECTIVE: To examine the participation of different neuropeptides in the human nasal mucosa of intermittent (seasonal) AR tissues in the allergic season. METHODS: Immunohistochemistry for substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and neuropeptide tyrosine (NPY) was related to the characterization of inflammatory cells in tissues of patients with seasonal AR (n=18). RESULTS: While there was a significant increase in the number of eosinophils present if compared with a control group, no changes occurred in mast cell numbers. Immunostaining was abundantly found in different nerve fibre populations of both groups. SP expression was significantly increased in mucosal nerve fibres of patients with intermittent (seasonal) AR. Also, significantly increased numbers of VIP- and NPY-immunoreactive nerve fibres were found in biopsies of rhinitis patients in comparison with sections of normal human nasal mucosa. In contrast, CGRP expression did not change significantly. CONCLUSION: The increase of neuropeptide expression in mucosal nerve fibres indicates a major role of the autonomous mucosal innervation in the pathophysiology of intermittent (seasonal) AR.

Biopsy↗

Nerve growth factor-induced substance P in capsaicin-insensitive vagal neurons innervating the lower mouse airway.

BACKGROUND: Nerve growth factor (NGF) is elevated in allergic diseases such as bronchial asthma and can lead to an induction of substance P (SP) and related neuropeptides in guinea-pigs large-diameter, neurofilament-positive airway neurons. OBJECTIVE: In the present study, the effect of NGF on tyrosine kinase receptor trkA and the capsaicin receptor TRPV1 expression in airway-specific vagal sensory neurons located in the jugular-nodose ganglia complex (JNC) of mice was investigated. METHODS: Using retrograde neuronal tracing in combination with double-labelling immunohistochemistry, SP, trkA- and TRPV1-receptor expression was examined in airway-specific sensory neurons of BALB/c mice before and after NGF treatment. RESULTS: NGF injected into the lower airway was able to induce SP (13.0+/-2.03% vs. 5.9+/-0.33%) and trkA expression (78+/-2.66% vs. 60+/-2.11%) in larger diameter (>25 microm), capsaicin-insensitive and trkA-positive vagal sensory neurons that were retrograde-labelled with Fast Blue dye from the main stem bronchi. CONCLUSION: Based on the extent of SP and trkA co-expression in airway-specific neurons by NGF treatment, the present study suggests that, following a peripheral activation of trkA receptor on SP afferent by NGF which is elevated in allergic inflammation, there may be trkA-mediated SP induction to mediate neurogenic airway inflammation.

Animals↗

Expression of tyrosine hydroxylase and neuropeptide tyrosine in mouse sympathetic airway-specific neurons under normal situation and allergic airway inflammation.

BACKGROUND: The traditional neurotransmitter catecholamine and the neuropeptide tyrosine in sympathetic airway nerves have been proposed to be involved in the pathogenesis of airway diseases. OBJECTIVE: The aim of the present study was to investigate the effect of allergic airway inflammation on the expression of catecholamine enzyme tyrosine hydroxylase (TH), neuropeptide tyrosine (NPY) and tachykinins in mouse sympathetic airway ganglia. METHODS: Using neuronal tracing in combination with immunohistochemistry, the present study was designed to characterize TH, NPY and tachykinin profiles of superior cervical (SCG) and stellate ganglia after allergen challenge. RESULTS: The vast majority of fast blue-labelled SCG neurons (allergen: 97.5+/-1.22% (mean+/-SEM) vs. controls: 94.5+/-1.48%, P=0.18) and stellate neurons (allergen: 95.3+/-1.01% vs. controls: 93.6+/-1.33%, P=0.34) were immunoreactive for TH. Of the TH immunoreactive and fast blue-labelled SCG neurons, 52.0+/-1.01% allergen vs. 51.2+/-3.58% controls (P=0.83) and stellate neurons, 57.3%+/-0.97 allergen vs. 56.4+/-1.65% controls (P=0.64) were positive for TH only but not NPY, whereas 45.3+/-1.05% allergen vs. 43.3+/-1.18% controls (P=0.47) of fast blue-labelled SCG neurons and 37.9+/-0.86% allergen vs. 37.1+/-1.24% controls (P=0.62) of fast blue-labelled stellate neurons were immunoreactive for both TH and NPY immunoreactivities. There was a trend of an increase, but not significant one, in the percentage of TH-/NPY-immunoreactive and fast blue-labelled neurons in allergen-treated animals in comparison with the controls. Tachykinins, however, were not expressed by sympathetic neurons and were also not induced in sympathetic neurons after allergen challenge. CONCLUSION: The present study indicates that allergic airway inflammation does not alter the expression of noradrenalin and NPY in sympathetic ganglia and also shows that sympathetic neurons do not respond to allergic airway inflammation with tachykinins induction. However, a participation of catecholamine and NPY in the pathogenesis of allergic airway inflammation cannot be excluded in the present study as a higher neurotransmitter output per neuron following allergen challenge could be possible.

Allergens↗

Neurogenic mechanisms in bronchial inflammatory diseases.

Neurogenic inflammation encompasses the release of neuropeptides from airway nerves leading to inflammatory effects. This neurogenic inflammatory response of the airways can be initiated by exogenous irritants such as cigarette smoke or gases and is characterized by a bi-directional linkage between airway nerves and airway inflammation. The event of neurogenic inflammation may participate in the development and progression of chronic inflammatory airway diseases such as allergic asthma or chronic obstructive pulmonary disease (COPD). The molecular mechanisms underlying neurogenic inflammation are orchestrated by a large number of neuropeptides including tachykinins such as substance P and neurokinin A, or calcitonin gene-related peptide. Also, other biologically active peptides such as neuropeptide tyrosine, vasoactive intestinal polypeptide or endogenous opioids may modulate the inflammatory response and recently, novel tachykinins such as virokinin and hemokinins were identified. Whereas the different aspects of neurogenic inflammation have been studied in detail in laboratory animal models, only little is known about the role of airway neurogenic inflammation in human diseases. However, different functional properties of airway nerves may be used as targets for future therapeutic strategies and recent clinical data indicates that novel dual receptor antagonists may be relevant new drugs for bronchial asthma or COPD.

Animals↗

Animal models of allergic and inflammatory conjunctivitis.

Allergic eye diseases are complex inflammatory conditions of the conjunctiva with an increasing prevalence and incidence. The diseases are often concomitant with other allergic diseases such as allergic rhinitis, atopic dermatitis and allergic asthma. Despite the disabling and prominent symptoms of ocular allergies, they are less well studied and further insights into the molecular basics are still required. To establish new therapeutic approaches and assess immunological mechanisms, animal models of ocular allergies have been developed in the past years. The major forms of allergic ocular diseases, seasonal and perennial allergic conjunctivitis, vernal and atopic keratoconjunctivitis and giant papillary conjunctivitis, each have different pathophysiological and immunological components. In contrast to these distinct entities, the current animal models are based on the sensitization against a small number of allergens such as ovalbumin, ragweed pollen or major cat allergens and consecutive challenge. Different animal species have been used so far. Starting with guinea-pig models of allergic conjunctivitis to assess pharmacological aspects, new models including rats and mice have been developed which mimic major features of ocular allergy. The presently preferred species for the investigation of the immunological basis of the disease is represented by murine models of allergic conjunctivitis. In the future, combined ocular, nasal and aerosolic challenges with allergens may provide a model of allergy that encompasses simultaneously the target organs eye, nose and airways with conjunctivitis, rhinitis and asthma.

Allergens↗

Fundamentals of pulmonary drug delivery.

Aerosol administration of peptide-based drugs plays an important role in the treatment of pulmonary and systemic diseases and the unique cellular properties of airway epithelium offers a great potential to deliver new compounds. As the relative contributions from the large airways to the alveolar space are important to the local and systemic availability, the sites and mechanism of uptake and transport of different target compounds have to be characterized. Among the different respiratory cells, the ciliated epithelial cells of the larger and smaller airways and the type I and type II pneumocytes are the key players in pulmonary drug transport. With their diverse cellular characteristics, each of these cell types displays a unique uptake possibility. Next to the knowledge of these cellular aspects, the nature of aerosolized drugs, characteristics of delivery systems and the depositional and pulmonary clearance mechanisms display major targets to optimize pulmonary drug delivery. Based on the growing knowledge on pulmonary cell biology and pathophysiology due to modern methods of molecular biology, the future characterization of pulmonary drug transport pathways can lead to new strategies in aerosol drug therapy.

Administration, Inhalation↗