Effect of endothelin antagonism on the production of cytokines in eosinophilic airway inflammation

Endothelin (ET)-1 has been launched as an important mediator in bronchial a sthma, which is an eosinophilic airway inflammation. However, the interplay between ET-1 and other proinflammatory mediators during the development of airway inflammation has not been elucidated. We wanted to study 1) whether the production of ET-1 precedes the production of other proinflammatory me diators and 2) whether ET-1 stimulates the production of these mediators wi thin the airways. These hypotheses were studied during the development of a n eosinophilic airway inflammation in rats. The increase in ET-1 mRNA level in lung tissue preceded the increase in mRNA levels of tumor necrosis fact or-alpha, interleukin (IL)-1 beta, and IL-8. Treatment of the animals with the ET receptor antagonist bosentan resulted in a substantial decrease in t he concentrations of tumor necrosis factor-alpha, IL-4, IL-1 beta, interfer on-gamma, and ET-1 in bronchoalveolar lavage fluid. In conclusion, the synt hesis of ET-1 as measured by increased mRNA level precedes the synthesis of other proinflammatory cytokines of importance for the development of an eo sinophilic airway inflammation, and ET antagonism inhibits the production o f these mediators within the airways. Whether treatment with ET antagonists will prove beneficial for patients with eosinophilic airway inflammations like bronchial asthma is not yet known.