Bradykinin B1 receptor antagonist R954 inhibits eosinophil activation/proliferation/migration and increases TGF-β and VEGF in a murine model of asthma

In the present study the effects of bradykinin receptor antagonists were investigated in a murine model of asthma using BALB/c mice immunized with ovalbumin/alum and challenged twice with aerosolized ovalbumin. Twenty four hours later eosinophil proliferation in the bone marrow, activation (lipid bodies formation), migration to lung parenchyma and airways and the contents of the pro-angiogenic and pro-fibrotic cytokines TGF-β and VEGF were determined. The antagonists of the constitutive B2 (HOE 140) and inducible B1 (R954) receptors were administered intraperitoneally 30 min before each challenge. In sensitized mice, the antigen challenge induced eosinophil proliferation in the bone marrow, their migration into the lungs and increased the number of lipid bodies in these cells. These events were reduced by treatment of the mice with the B1 receptor antagonist. The B2 antagonist increased the number of eosinophils and lipid bodies in the airways without affecting eosinophil counts in the other compartments. After challenge the airway levels of VEGF and TGF-β significantly increased and the B1 receptor antagonist caused a further increase. By immunohistochemistry techniques TGF-β was found to be expressed in the muscular layer of small blood vessels and VEGF in bronchial epithelial cells. The B1 receptors were expressed in the endothelial cells. These results showed that in a murine model of asthma the B1 receptor antagonist has an inhibitory effect on eosinophils in selected compartments and increases the production of cytokines involved in tissue repair. It remains to be determined whether this effects of the B1 antagonist would modify the progression of the allergic inflammation towards resolution or rather towards fibrosis.