Bradykinin B(1) receptor antagonist R954 inhibits eosinophil activation/proliferation/migration and increases TGF-beta 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-beta and VEGF were determined. The antagonists of the constitutive B(2) (HOE 140) and inducible B(1) (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 B(1) receptor antagonist. The B(2) 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-beta significantly increased and the B(1) receptor antagonist caused a further increase. By immunohistochemistry techniques TGF-beta was found to be expressed in the muscular layer of small blood vessels and VEGF in bronchial epithelial cells. The B(1) receptors were expressed in the endothelial cells. These results showed that in a murine model of asthma the B(1) 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 B(1) antagonist would modify the progression of the allergic inflammation towards resolution or rather towards fibrosis.

High vascular endothelial growth factor levels in NZW mice do not correlate with collagen deposition in allergic asthma.

BACKGROUND: Eosinophils contribute to the early features of allergic lung inflammation through the generation and release of a plethora of mediators. Eosinophil peroxidase (EPO) is one of the eosinophil granule proteins involved in the early response, but its participation in airway remodeling is not established. The present study addressed this question comparing an EPO-deficient mouse strain (NZW) with BALB/c and C57Bl/c strains. METHODS: Mice were immunized with ovalbumin/alum, challenged twice with ovalbumin aerosol, and lung responses were measured at day 22 or 28. Collagen, mucus and eosinophils were determined in lung sections stained with picrosirius, periodic acid-Schiff or hematoxylin-eosin; transforming growth factor-beta and vascular endothelial growth factor were determined by ELISA, lipid bodies by enumeration in osmium-stained eosinophils, and airway reactivity to methacholine in isolated lung preparations. RESULTS: NZW mice showed significantly less collagen around bronchi and blood vessels, less mucus and less eosinophils around bronchi. Eosinophil lipid body formation and airway hyperreactivity were comparable among strains. Levels of transforming growth factor-beta were also comparable; however, the NZW mice showed much higher levels of vascular endothelial growth factor, even under basal conditions. CONCLUSIONS: In allergic lung inflammation, the combination of EPO deficiency and overexpression of VEGF found in NZW mice is associated with less collagen deposition, less mucus and reduced tissue eosinophilia. Eosinophil activation and airway hyperreactivity in NZW mice were similar to the other strains.