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.
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 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.