[show abstract][hide abstract] ABSTRACT: Vasoactive intestinal polypeptide (VIP) is a putative neurotransmitter of the inhibitory non-adrenergic non-cholinergic nervous system and influences the mammalian airway function in various ways. Hence known for bronchodilatory, immunomodulatory and mucus secretion modulating effects by interacting with the VIP receptors VPAC1 and VPAC2, it is discussed to be a promising target for pharmaceutical intervention in common diseases such as COPD and bronchial asthma. Here we examined the expression and transcriptional regulation of VPAC1 in the lungs of allergic mice using an ovalbumin (OVA) -induced model of allergic asthma. Mice were sensitized to OVA and challenged with an OVA aerosol. In parallel a control group was sham sensitized with saline. VPAC1 expression was examined using RT-PCR and real time-PCR studies were performed to quantify gene transcription. VPAC1 mRNA expression was detected in all samples of OVA-sensitized and challenged animals and control tissues. Further realtime analysis did not show significant differences at the transcriptional level.Although the present studies did not indicate a major transcriptional regulation of VPAC1 in states of allergic airway inflammation, immunomodulatory effects of VPAC1 might still be present due to regulations at the translational level.
Journal of Occupational Medicine and Toxicology 10/2013; 8(1):28.
[show abstract][hide abstract] ABSTRACT: Animal models with a high predictive value for human trials are needed to develop novel human-specific therapeutics against respiratory diseases. The aim of the study was to examine lung function parameters in marmoset monkeys (Callithrix jacchus) that can be used to detect pharmacologically or provocation induced airway hyperresponsiveness. Therefore, a custom-made lung function device which allows application of defined aerosol doses during measurement was developed. It was hypothesized that LPS-challenged marmosets show airway hyperresponsiveness compared to non-challenged, healthy subjects. Invasive plethysmography was performed in twelve anesthetized, orotracheally intubated and spontaneously breathing marmosets. Pulmonary data of lung resistance (RL), dynamic compliance (Cdyn), midexpiratory flow (EF50), oesophageal pressure (Poes), minute volume (MV), respiratory frequency (f), and tidal volume (VT) were collected. Measurements were conducted at baseline conditions and under methacholine-induced bronchoconstriction. The measurement was repeated with the same group of animals after induction of an acute lung inflammation by intratracheal application of lipopolysaccharide (LPS). Provocative doses of methacholine to achieve a certain increase in RL were significantly lower after LPS administration. Airway hyperresponsiveness was demonstrated in the LPS treated compared to the naïve animals. The recorded lung function data provide ground for pre-clinical efficacy and safety testing of anti-inflammatory substances in the common marmoset, a new translational NHP model for LPS-induced lung inflammation.
[show abstract][hide abstract] ABSTRACT: Allergen-containing subpollen particles (SPP) are released from whole plant pollen upon contact with water or even high humidity. Because of their size SPP can preferentially reach the lower airways where they come into contact with surfactant protein (SP)-D. The aim of the present study was to investigate the influence of SP-D in a complex three-dimensional human epithelial airway model, which simulates the most important barrier functions of the epithelial airway. The uptake of SPP as well as the secretion of pro-inflammatory cytokines was investigated.
SPP were isolated from timothy grass and subsequently fluorescently labeled. A human epithelial airway model was built by using human Type II-pneumocyte like cells (A549 cells), human monocyte derived macrophages as well as human monocyte derived dendritic cells. The epithelial cell model was incubated with SPP in the presence and absence of surfactant protein D. Particle uptake was evaluated by confocal microscopy and advanced computer-controlled analysis. Finally, human primary CD4+ T-Cells were added to the epithelial airway model and soluble mediators were measured by enzyme linked immunosorbent assay or bead array.
SPP were taken up by epithelial cells, macrophages, and dendritic cells. This uptake coincided with secretion of pro-inflammatory cytokines and chemokines. SP-D modulated the uptake of SPP in a cell type specific way (e.g. increased number of macrophages and epithelial cells, which participated in allergen particle uptake) and led to a decreased secretion of pro-inflammatory cytokines.
These results display a possible mechanism of how SP-D can modulate the inflammatory response to inhaled allergen.
Respiratory research 01/2012; 13:8. · 3.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: Allergen-containing subpollen particles (SPP) are released from whole plant pollen upon contact with water or even high humidity. Because of their size SPP can preferentially reach the lower airways where they come into contact with surfactant protein (SP)-D. Our previous work demonstrated that SP-D increases the uptake of SPP by alveolar macrophages. In the present study, we investigated the uptake of SPP in human primary epithelial cells and the potential modulation by SP-D. The patho-physiological consequence was evaluated by measurement of pro-inflammatory mediators.
SPP were isolated from timothy grass and subsequently fluorescently labelled. Human primary bronchial epithelial cells were incubated with SPP or polystyrene particles (PP) in the presence and absence of surfactant protein D. In addition, different sizes and surface charges of the PP were studied. Particle uptake was evaluated by flow cytometry and confocal microscopy. Soluble mediators were measured by enzyme linked immunosorbent assay or bead array.
SPP were taken up by primary epithelial cells in a dose dependent manner. This uptake was coincided with secretion of Interleukin (IL)-8. SP-D increased the fraction of bronchial epithelial cells that bound SPP but not the fraction of cells that internalized SPP. SPP-induced secretion of IL-8 was further increased by SP-D. PP were bound and internalized by epithelial cells but this was not modulated by SP-D.
Epithelial cells bind and internalize SPP and PP which leads to increased IL-8 secretion. SP-D promotes attachment of SPP to epithelial cells and may thus be involved in the inflammatory response to inhaled allergen.
Respiratory research 01/2010; 11:83. · 3.64 Impact Factor