An endothelin receptor antagonist, SB-217242, inhibits airway hyperresponsiveness in allergic mice

Abstract

Within the airways, endothelin-1 (ET-1) can exert a range of prominent effects, including airway smooth muscle contraction, bronchial obstruction, airway wall edema, and airway remodeling. ET-1 also possesses proinflammatory properties and contributes to the late-phase response in allergic airways. However, there is no direct evidence for the contribution of endogenous ET-1 to airway hyperresponsiveness in allergic airways. Allergic inflammation induced in mice by sensitization and challenge with the house dust mite allergen Der P1 was associated with elevated levels of ET-1 within the lung, increased numbers of eosinophils within bronchoalveolar lavage fluid and tissue sections, and development of airway hyperresponsiveness to methacholine (P Ͻ 0.05, n ϭ 6 mice per group). Treatment of allergic mice with an endothelin receptor antagonist, SB-217242 (30 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), during allergen challenge markedly inhibited airway eosinophilia (bronchoalveolar lavage fluid and tissue) and development of airway hyperresponsiveness. These findings provide direct evidence for a mediator role for ET-1 in development of airway hyperresponsiveness and airway eosinophilia in Der P1-sensitized mice after antigen challenge. eosinophils; allergic inflammation THERE IS A GROWING BODY of evidence from human and animal studies supporting a mediator role for endothelin-1 (ET-1) in several characteristic features of the allergic airway response, including airway inflammation and variable airflow obstruction. In allergic asthmatic patients, increased ET-1 immunoreactivity has been demonstrated in the airway epithelium of bronchial biopsies and elevated levels of ET-1 have been detected in bronchoalveolar lavage fluid. Consistent with these findings, several recent studies in rats have demonstrated that allergic inflammation induced by ovalbumin or Sephadex is associated with an early increase in expression of lung prepro-ET-1 mRNA, increased ET-1 immunoreactivity in bronchial epithelium, and elevated ET-1 peptide levels in lung tissue and bronchoalveolar lavage fluid (11,31,32).Animal studies using ET-1 antibodies and endothelin receptor antagonists point to endogenous ET-1 contributing to several processes involved in the allergic inflammatory response. For example, the endothelin receptor antagonist BQ-123 reduced the late, but not the early, antigen-induced reduction in airflow response in allergic sheep (26) and guinea pigs (38). The involvement of ET-1 in the late-phase allergic response, which is associated with the migration of inflammatory cells into the airways, is in accord with the recent findings from several independent groups that endothelin receptor antagonists inhibit the antigeninduced influx of eosinophils into the airways and bronchoalveolar lavage fluid (12,15,31).In addition to its effects on eosinophil recruitment into the airways, ET-1 has many other purported actions within the airways that may promote inflammation and airflow obstruction. For example, ET-1 stimulates the release of a range of proinflammator...

Alteration of airway responsiveness mediated by receptors in ovalbumin-induced asthmatic E3 rats

“…Thus, the endothelin-1 system is very important to airway hyperresponsiveness. ET A and ET B receptor antagonists inhibit airway hyperreactivity [30] , supporting our results.…”

Endothelin A receptor antagonist modulates lymphocyte and eosinophil infiltration, hyperreactivity and mucus in murine asthma

“…receptor antagonist, BQ123. This is in agreement with Henry et al [21] who showed that another ET A receptor antagonist, SB217242, inhibited the development of hyperreactivity in mice sensitized to house dust mite allergen and challenged with the allergen. We showed here that the ET A receptor antagonist reduced the airway hyperreactivity while it increased the Tγδ + cell infiltration.…”

“…The antagonist of ET A receptor markedly reduced the lung eosinophilia, corroborating previous reports [21][22][23].…”

Inhibition of phosphodiesterase activity, airway inflammation and hyperresponsiveness by PDE4 inhibitor and glucocorticoid in a murine model of allergic asthma

“…MCh dosages (0.125 mg/kg to 2 mg/kg, i.v.) were described previously (Henry et al, 2002). The effects of piclamilast and dexamethasone were determined by comparing the changes in R L and C dyn after drug treatment with the mean of MCh response alone in the same mouse on previous and successive control periods.…”