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

Abstract

Cite this as: H. D. Lauenstein, D. Quarcoo, L. Plappert, C. Schleh, M. Nassimi, C. Pilzner, S. Rochlitzer, P. Brabet, T. Welte, H. G. Hoymann, N. Krug, M. Müller, E. A. Lerner, A. Braun and D. A. Groneberg, Clinical & Experimental Allergy, 2011 (41) 592–601.SummaryBackground Bronchial asthma is characterized by airway inflammation and reversible obstruction. Since the gold standard of therapy, a combination of anti‐inflammatory corticosteroids and bronchodilatory β2 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.

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