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

Abstract

Summary 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.

Expression of VPAC1 in a murine model of allergic asthma

“…Interestingly, the VPAC1 related receptor PAC1 was recently shown to be differentially expressed in a murine model of ovalbumin-induced asthma [17]. In this study an increased PAC1R mRNA expression was present in lung tissue under allergic conditions.…”

Stress and asthma: Novel insights on genetic, epigenetic, and immunologic mechanisms

“…After induction of experimental asthma, MS rats had greater number of eosinophils in broncho-alveolar lavage than controls or HA rats (P =0.002). In HA rats, induction of experimental asthma was associated with markedly increased levels of adreno-corticotropin compared with the MS or control groups (P for one-way analysis of variance=0.02) 47 . Taken together, these results suggest that early post-natal stressors have effects on the “neuroendocrine immune system” lasting into adult life.…”

“…However, the biological plausibility of our results is supported by experimental models showing that PACAP acts as endogenous bronchodilator, relaxing airway smooth muscle 44,45 . Moreover, PACAP protects against endotoxin-induced allergic airway inflammation (AAI) in rodents 46 , in which the PAC1 receptor mediates anti-inflammatory effects in AAI 47 . Together with these experimental findings, our results suggest that genetic and epigenetic variation in a susceptibility gene for PTSD and childhood anxiety ( ADCYAP1R1 ) is implicated in the pathogenesis of asthma in children disproportionately exposed to violence or traumatic events, such as Puerto Ricans.…”

Neuroendocrine cells derived chemokine vasoactive intestinal polypeptide (VIP) in allergic diseases

“…However, the study performed by Lauenstein et al, (2011) suggested that PAC1 receptor mediates anti-inflammatory effects in allergic airway inflammation. Thus, PAC1 receptor agonists may be a promising candidate in airway allergic diseases such as bronchial asthma [53]. …”