bq-123 and Bronchial-Hyperreactivity

Levels of endothelins are particularly high in the lung, and there is evidence that these peptides are involved in asthma. Asthma is a chronic inflammatory disease associated with lymphocyte infiltration. In the present study, we used a murine model of asthma to investigate the role of endothelins in lymphocyte and eosinophil infiltration into the airway hyperreactivity and mucus secretion. Sensitized C57Bl/6 mice were treated with endothelin ETA receptor antagonist (BQ123) or endothelin ETB receptor antagonist (BQ788) 30 min before an antigen aerosol challenge. After 24 h, dose response curves to methacholine were performed in isolated lungs, FACS analysis of lymphocytes and eosinophil counts were performed in bronchoalveolar lavage fluid and mucus index was determined by histopathology. In sensitized and antigen-challenged mice there is a marked increase in the T CD4+, T CD8+, B220+, Tgammadelta+ and NK1.1+ lymphocyte subsets. Treatment with BQ123 further increased these cell populations. The number of eosinophils, airway hyperreactivity and mucus were all reduced by BQ123 treatment. The BQ 788 had no significant effect on the parameters analyzed. Treatment with BQ123 reduced the endothelin concentration in lung homogenates, suggesting that endothelins exert a positive feedback on their synthesis. We show here that in murine asthma the ETA receptor antagonist up-regulates lymphocyte infiltration and reduces eosinophils, hyperreactivity and mucus.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Endothelin A Receptor Antagonists; Eosinophils; Lung; Lymphocyte Subsets; Male; Methacholine Chloride; Mice; Mice, Inbred C57BL; Mucus; Ovalbumin; Peptides, Cyclic

Endothelin A (ETA)-receptors mediate ET-1 contractions of ovine airway smooth muscle. Therefore, the ETA-receptor antagonist, BQ-123, was used to test the hypothesis that ET-1 contributes to antigen-induced airway responses in sheep allergic to Ascaris suum. We first established the protective effect of BQ-123 by demonstrating that BQ-123 given as an aerosol (0.3 or 1.0 mg/kg in 3 ml buffer) or by continuous intravenous infusion (100 micrograms.kg-1.min-1) significantly blocked the bronchoconstriction to aerosolized ET-1 (0.2-200 micrograms/ml). To determine whether ET-1 contributed to antigen-induced airway responses, BQ-123 was given either as an intravenous infusion (100 micrograms.kg-1.min-1) beginning 30 min before and continuing for 8 h after antigen challenge or as an aerosol (1 mg/kg in 3 ml buffer) 30 min before and 4, 8, and 24 h after antigen challenge. Neither treatment with intravenous infusion nor aerosolized BQ-123 blocked the immediate antigen-induced bronchoconstriction, but both treatments significantly reduced the late response (approximately 50%). The treatments with aerosolized BQ-123 also blocked the antigen-induced airway hyperresponsiveness to inhaled carbachol seen 24 h after challenge. Subsequently, we found that sheep developed airway hyperresponsiveness to inhaled carbachol at 4 and 24 h after ET-1 challenge, an effect that was blocked by aerosolized BQ-123. We conclude that in allergic sheep 1) aerosolized ET-1 causes bronchoconstriction, in part, by stimulation of ETA-receptors, 2) ET-1 is released in the airways after antigen challenge, and 3) this peptide contributes to the severity of the allergic responses, probably by increasing airway smooth muscle responsiveness.

Topics: Administration, Inhalation; Animals; Antigens, Helminth; Ascaris suum; Bronchial Hyperreactivity; Endothelin Receptor Antagonists; Endothelins; Infusions, Intravenous; Peptides, Cyclic; Receptor, Endothelin A; Receptors, Endothelin; Sheep