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


CONCLUSIONS
PAC1R agonists may represent a promising target for an anti-inflammatory therapy in airway diseases such as bronchial asthma.
Department of Immunology, Allergology and Immunotoxicology, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
H D
HD
Lauenstein
D
D
Quarcoo
L
L
Plappert
C
C
Schleh
M
M
Nassimi
C
C
Pilzner
S
S
Rochlitzer
P
P
Brabet
T
T
Welte
H G
HG
Hoymann
N
N
Krug
M
M
Müller
E A
EA
Lerner
A
A
Braun
D A
DA
Groneberg
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D007073:Immunoglobulin E / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000893:Anti-Inflammatory Agents; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D007073:Immunoglobulin E