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

Abstract 

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 30min 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.

Keywords: TGF-β, VEGF, Bradykinin, Eosinophils, Asthma