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Biomedical subjects

David A Groneberg

Publications and source records attributed to David A Groneberg.

At least 19 recordsLinked to original sources
PubMed2006

Role of lipid rafts in membrane delivery of renal epithelial Na+-K+-ATPase, thick ascending limb.

Lipid rafts are cholesterol- and shingolipid-enriched membrane microdomains implicated in membrane signaling and trafficking. To assess renal epithelial raft functions through the characterization of their associated membrane proteins, we have isolated lipid rafts from rat kidney by sucrose gradient fractionation after detergent treatment. The low-density fraction was enriched in cholesterol, sphingolipid, and flotillin-1 known as lipid raft markers. Based on proteomic analysis of the low-density fraction, the protein with the highest significance score was the alpha-subunit of Na(+)-K(+)-ATPase (NKA), whose raft association was validated by simultaneous immunoblotting. The beta-subunit of NKA was copurified from the low-density fraction. To test the role of lipid rafts in sorting and membrane delivery of renal-transporting epithelia, we have chosen to study thick ascending limb (TAL) epithelium for its high NKA activity and the property to be stimulated by antidiuretic hormone (ADH). Cultured rabbit TAL cells were studied. Cholesterol depletion and detergent extraction at warmth caused a shift of NKA to the higher-density fractions. Comparative preparations from blood monocytes revealed the absence of NKA from rafts in these nonpolarized cells. Short-term exposure of rabbit TAL cells to ADH (1 h) caused translocation and enhanced raft association of NKA via cAMP activation. Preceding cholesterol depletion prevented this effect. TAL-specific, glycosylphosphatidylinositol-anchored Tamm Horsfall protein was copurified with NKA in the same raft fraction, suggesting functional interference between these products. These results may have functional implications regarding the turnover, trafficking, and regulated surface expression of NKA as the major basolateral ion transporter of TAL.

Animals↗
PubMed2006

Evaluation of renal functional parameters in different settings of isolated organ hemoperfusions.

Isolated porcine kidneys are commonly used to study physiological and pathophysiological aspects of renal homeostasis but standardized evaluation procedures of renal function in this model do not exist so far. A double-logarithmical nomogram is established for filtration and reabsorption functions in isolated and hemoperfused porcine kidneys using different perfusion settings. Model validity was demonstrated by the levels of urine flow and sodium excretion showing expected alteration levels of lowering in the ADH-group and increasing in the furosemide-group of isolated kidneys. Creatinine-clearance values were in constant ranges within each specific perfusion group as indicated by the nomogram procedure. The present studies used a nomogram method to analyze the effects of different renal perfusion settings in a porcine model of kidney perfusion. The method may be of use to differentiate various kidney perfusion parameters both at the experimental and clinical levels.

Animals↗
PubMed2006

The toxicity of cadmium and resulting hazards for human health.

Cadmium (Cd) has been in industrial use for a long period of time. Its serious toxicity moved into scientific focus during the middle of the last century. In this review, we discuss historic and recent developments of toxicological and epidemiological questions, including exposition sources, resorption pathways and organ damage processes.

Journal Article↗
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

Asthma and COPD.

The two obstructive airway diseases bronchial asthma and chronic obstructive pulmonary disease (COPD) represent major global causes of disability and death, and COPD is estimated to become the third most common cause of death by 2020. The structural and pathophysiologic findings in both diseases appear to be easily differentiated in the extremes of clinical presentation. However, a significant overlap may exist in individual patients regarding features such as airway wall thickening on computer tomography or reversibility and airway hyperresponsiveness in lung function tests. Airway inflammation differs between the two diseases. In bronchial asthma, airway inflammation is characterized in most cases by an increased number of activated T-lymphocytes, particularly CD4+ Th2 cells, and sometimes eosinophils and mast cells. The most notable difference of chronic severe asthma compared with mild to moderate asthma is an increased number of neutrophils. In stable COPD, airway inflammation is characterized by an increased number of T-lymphocytes, particularly CD8+ T cells, macrophages and neutrophils. With the progression of the disease severity, macrophage and neutrophil numbers increase. Although there may be a partial overlap between asthma and COPD in some patients, the differences in functional, structural and pharmacological features clearly demonstrate the consensus that asthma and COPD are different diseases along all their stages of severity.

Animals↗
PubMed2006

Novel strategies of aerosolic pharmacotherapy.

The pulmonary administration of drugs plays a crucial role in the management of various respiratory and systemic diseases. While the cellular properties of airway epithelial cells offer a great potential to deliver drugs into the lungs or the circulation, only little is known about the exact transport pathways. Recently, the high-affinity proton-coupled drug and peptide transporter PEPT2 was identified in the human respiratory tract. The expression of transporter mRNA and protein was localized to the airway epithelium and alveolar type II pneumocytes. In addition, transport studies revealed transporter-mediated uptake of substrates into epithelial cells indicating that the transporter is the molecular basis for the transport of peptides and peptidomimetic drugs in pulmonary epithelial cells. Since genotype analysis revealed no significant differences amongst different transporter genotypes concerning expression and function, the transporter displays an interesting novel target for pulmonary delivery of drugs.

Administration, Inhalation↗
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

Nanomedicine for respiratory diseases.

Nanotechnology provides new materials in the nanometer range with many potential applications in clinical medicine and research. Due to their unique size-dependent properties nanomaterial such as nanoparticles offer the possibility to develop both new therapeutic and diagnostic tools. Thus, applied nanotechnology to medical problems--nanomedicine--can offer new concepts that are reviewed. The ability to incorporate drugs into nanosystems displays a new paradigm in pharmacotherapy that could be used for cell-targeted drug delivery. Nontargeted nanosystems such as nanocarriers that are coated with polymers or albumin and solid lipid particles have been used as transporter in vivo. However, nowadays drugs can be coupled to nanocarriers that are specific for cells and/or organs. Thus, drugs that are either trapped within the carriers or deposited in subsurface oil layers could be specifically delivered to organs, tumors and cells. These strategies can be used to concentrate drugs in selected target tissues thus minimizing systemic side effects and toxicity. In addition to these therapeutic options, nanoparticle-based "molecular" imaging displays a field in which this new technology has set the stage for an evolutionary leap in diagnostic imaging. Based on the recent progress in nanobiotechnology there is potential for nanoparticles and -systems to become useful tools as therapeutic and diagnostic tools in the near future.

Animals↗
PubMed2006

Nanoparticle-based diagnosis and therapy.

Nanoparticles are at the leading edge of the rapidly developing field of material science in nanotechnology with many potential applications in clinical medicine and research. Due to their unique size-dependent properties nanoparticles offer the possibility to develop both new therapeutic and diagnostic tools. The ability to incorporate drugs into nanosystems displays a new paradigm in pharmacotherapy that could be used for cell-targeted drug delivery. Nontargeted nanosystems such as nanocarriers that are coated with polymers or albumin and solid lipid particles have been used to transport a large number of compounds. However, nowadays drugs can be coupled to nanocarriers that are specific for cells and/or organs. Thus, drugs that are either trapped within the carriers or deposited in subsurface oil layers could be specifically delivered to organs, tumors and cells. These strategies can be used to concentrate drugs in selected target tissues thus minimizing systemic side effects and toxicity. In addition to these therapeutic options, nanoparticle-based "molecular" imaging displays a field in which this new technology has set the stage for an evolutionary leap in diagnostic imaging. Based on the recent progress in nanobiotechnology, nanoparticles have the potential to become useful tools as therapeutic and diagnostic tools in the near future.

Animals↗
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

The cysteinyl-leukotriene-1 receptor antagonist zafirlukast is a potent secretagogue in rat and human airways.

Cysteinyl-leukotriene-1 receptor antagonists are important tools in the therapy of asthma. Although many studies have been performed concerning their effects on airway smooth muscle tone, there are no basic data on their effects on airway secretions. Therefore, we assessed the effects of zafirlukast and montelukast on rat tracheal secretion by quantification of secreted 35S04 labelled mucus macromolecules, and determined the influence of the arachidonic acid pathway using the modified Ussing chamber technique. Zafirlukast (432+/-89.99%) and montelukast (167+/-16.74%) stimulated rat tracheal secretion. This was abolished by application of eicosatetraenoic acid, an inhibitor of the arachidonic acid metabolism. Whereas inhibition of cyclooxygenase did not show any significant effect on zafirlukast induced secretion, blockade of the 5-lipoxygenase pathway markedly reduced the secretagogue effects. Furthermore, inhibition of phosphatidylinositol-3-kinase completely inhibited the effects elicited by zafirlukast. Additional experiments revealed secretagogue effects of zafirlukast also in human bronchial tissue. In conclusion, zafirlukast is a potent inducer of tracheal secretion. Obviously, these effects are induced by involvement of a phosphatidylinositol-3-kinase dependent pathway mediated by products of the arachidonic acid metabolism.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed2005

Parental tobacco smoking is associated with augmented IL-13 secretion in children with allergic asthma.

BACKGROUND: Exposure to environmental tobacco smoke (ETS) has been shown to increase symptoms of allergic bronchial asthma, but direct effects on the expression of inflammatory markers have not been demonstrated thus far. OBJECTIVE: The aim of this study was to assess the correlation of ETS exposure with the expression of proinflammatory mediators in airway secretions, including IFN-gamma and IL-12, as well as IL-5 and IL-13, in allergic asthmatic schoolchildren and healthy control subjects. METHODS: By using the nasopharyngeal aspiration technique, airway secretions were collected from 24 atopic children with asthma (age, 6-16 years) and 26 healthy control subjects, and the concentration of cytokines was measured with immunoenzymatic methods. RESULTS: IL-13 levels were highly increased in patients with asthma (P < .005), and parental tobacco smoke resulted in a significant increase in airway IL-13 secretion in these children compared with that seen in nonexposed children and healthy control subjects (median, 860 pg/mL vs 242 pg/mL and 125 pg/mL, respectively). Furthermore, a positive correlation between IL-13 levels and serum IgE concentrations (r(s) = 0.55) was found in children with allergic asthma. CONCLUSIONS: These results indicate that ETS augments the expression and secretion of IL-13 in allergic asthma and that nasopharyngeal aspiration is a suitable method to assess cytokine measurements in airways in children. Measurements of IL-13 in secretions might be taken into account as a noninvasive marker of airway inflammation and to assess the detrimental effects of ETS.

Adolescent↗
PubMed2005

Regulation of NGF and BDNF by dexamethasone and theophylline in human peripheral eosinophils in allergics and non-allergics.

BACKGROUND: Recent studies have shown that the neurotrophins NGF and BDNF are produced by eosinophils. The influence of neurotrophins in allergic diseases including asthma has been described. The regulation by pharmacological substance remains unclear. OBJECTIVES: The aim of this study was to assess whether approved pharmacological substances in the treatment of asthma such as corticosteroids or theophylline regulate neurotrophins on a cellular level. METHODS: Eosinophils were purified by negative immunoselection from allergics and non-allergic donors. Eosinophils were incubated with dexamethasone and theophylline and supernatants were collected for measurement of neurotrophic factors. The content of neurotrophins in eosinophil lysates was determined by ELISA. Regulation of stored NGF and BDNF was demonstrated by Western-blotting and flow cytometry while influence on transcription level was demonstrated by RT-PCR. RESULTS: Eosinophils produce and release the neurotrophins NGF and BDNF at different levels in allergics and non-allergics. Dexamethason lead to a significant downregulation of NGF in eosinophils of allergics. The levels of BDNF were not significantly reduced. Theophylline did not influence the levels of NGF nor BDNF significantly. CONCLUSIONS: The production of the neurotrophin NGF was downregulated by an established substance such as dexamethasone. This might further contribute to the pharmacological potential of corticosteroids in allergic asthma.

Anti-Inflammatory Agents↗
PubMed2005

Albumin and hydroxyethyl starch 130 kDa/0.4 improve filter clearance and haemocompatibility in haemo- and plasmafiltration--an in vitro study.

BACKGROUND: Apart from their standard applications, haemofiltration (HF) and plasmafiltration (PF) may provide helpful therapy for sepsis, multiple organ- and acute liver-failure. Some colloids cause either decreases or increases in blood cell agglomeration. We hypothesized that solutions which reduce cell aggregability may lead to both improved filter clearance and better haemocompatibility due to decreasing rates of clogged hollow fibres. METHODS: Heparinized porcine blood (5 IU/ml) was used in an in vitro circuit. The filter types tested were from GAMBRO: HF66D (effective membrane surface: 0.6 m2) and PF1000N (effective membrane surface: 0.15 m2). Albumin (ALB), hydroxyethyl starch (HES) 200/0.5, HES 130/0.4, gelatin (GEL) or normal saline (0.9%) were added to the blood (n = 6/group). Recirculation systems were run for 2 h. Spontaneous haemolysis and filter resistance >420 mmHg were selected as indications of maximal flow rates. Sieving coefficients were determined for 17 parameters at the lowest and highest blood flows and filtration rate. RESULTS: Based on the filter types used, supplementation of ALB and HES130/0.4 led to an improved filter clearance without increasing the number of clogged capillary membranes or causing impaired haemocompatibility. Sieving coefficients for most solutes were independent of volume substitute and flow rate. Haemocompatibility and filter clearance deteriorated after addition of HES200 or GEL to the blood. CONCLUSIONS: Under standardized in vitro conditions, we found that colloids which reduce cell aggregability cause improved HF- and PF-performance. This phenomenon may provide new options for higher clearances and may lead to new concepts in low dose anticoagulation.

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↗