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Pituitary adenylate cyclase-activating peptide receptor 1 mediates anti-inflammatory effects in allergic airway inflammation in mice

 
: Lauenstein, H.D.; Quarcoo, D.; Plappert, L.; Schleh, C.; Nassimi, M.; Pilzner, C.; Rochlitzer, S.; Brabet, P.; Welte, T.; Hoymann, H.G.; Krug, N.; Müller, M.; Lerner, E.A.; Braun, A.; Groneberg, D.A.

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Clinical & experimental allergy 41 (2011), No.4, pp.592-601
ISSN: 0954-7894
ISSN: 0960-2178
English
Journal Article
Fraunhofer ITEM ()
airway inflammation; mouse model; Neuropeptide; PACAP; VIP; allergy; asthma

Abstract
Background Bronchial asthma is characterized by airway inflammation and reversible obstruction. Since the gold standard of therapy, a combination of anti-inflammatory corticosteroids and bronchodilatory beta(2) agonists, has recently been discussed to be related to an increased mortality, there is a need for novel therapeutic pathways.
Objective A new experimental concept that encompasses the vasoactive intestinal peptide/pituitary adenylate cyclase activating peptide (PACAP) family of receptors by demonstrating the anti-inflammatory effects of the PACAP receptor 1 (PAC1R) in a murine model of allergic asthma is described.
Methods PAC1R expression was investigated in lung tissue and isolated dendritic cells (DCs) via real-time PCR. Ovalbumin (OVA)-induced asthma models were used in PAC1R-deficient mice and BALB/c mice treated with PAC1R agonist maxadilan (MAX). Bronchoalveolar lavages have been performed and investigated at the cellular and cytokine levels. Fluorescence staining of a frozen lung section has been performed to detect eosinophil granulocytes in lung tissue. Plasma IgE levels have been quantified via the ELISA technique. Lung function was determined using head-out body plethysmography or whole-body plethysmography.
Results Increased PAC1R mRNA expression in lung tissue was present under inflammatory conditions. PAC1R expression was detected on DCs. In OVA-induced asthma models, which were applied to PAC1R-deficient mice (PAC1R(-/-) ) and to BALB/c mice treated with the specific PAC1R agonist MAX, PAC1R deficiency resulted in inflammatory effects, while agonistic stimulation resulted in anti-inflammatory effects. No effects on lung function were detected both in the gene-depletion and in the pharmacologic studies. In summary, here, we demonstrate that anti-inflammatory effects can be achieved via PAC1R.
Conclusion PAC1R agonists may represent a promising target for an anti-inflammatory therapy in airway diseases such as bronchial asthma

: http://publica.fraunhofer.de/documents/N-149016.html