Contribution of upregulated airway endothelin-1 expression to airway smooth muscle and epithelial cell DNA synthesis after repeated allergen exposure of sensitized Brown-Norway rats

Abstract

Endothelin-1 is a potent bronchoconstrictor peptide with proinflammatory and growth-promoting properties. After exposure of sensitized Brown-Norway rats to six repeated ovalbumin exposures, there was an increase in pro-endothelin (ET)-1 messenger RNA compared with saline-exposed control rats 24 h after the final exposure (P < 0.01). ET-1 immunoreactivity was increased sixfold in the bronchial epithelium of the larger conducting airways in the repeated allergen-exposed rats (P < 0.001). After repeated allergen exposure, there were increased rates of DNA synthesis in the airway smooth muscle (ASM) cells (P < 0.001) and epithelial cells (P < 0.001) compared with saline-exposed controls, as measured by bromodeoxyuridine incorporation. Treatment with a dual endothelin A and B (ET(A+B)) receptor antagonist caused a significant attenuation in both ASM (P < 0.001) and epithelial cell (P < 0.001) bromodeoxyuridine incorporation compared with the allergen-challenged and vehicle-treated group. The dual ET(A+B) antagonist attenuated eosinophil recruitment into the airways (P < 0.05) but had no significant effect on increased bronchial reactivity to acetylcholine in allergen-exposed rats. Increased levels of ET-1 in the airways may contribute to inflammation and ASM and epithelial cell DNA synthesis after repeated allergen exposure. Such processes may underlie increased proliferation of resident cells leading to airway wall remodeling in asthmatics.