Endothelin (ET) has strong bronchoconstrictor properties, stimulate mucus secretion and mucosal edema, and may also exert proinflammatory effects. Therefore, ET may play a pathogenic role in inflammatory airway diseases such as bronchial asthma. The production and localization of ET and the effect of blocking ET receptors was investigated in rats during airway inflammation induced by intratracheal instillation of dextran (Sephadex). We observed a considerable increase in the concentration of ET in bronchoalveolar lavage fluid (BALF) during the early phase of inflammation, with an increase from 2.2 +/- 0.6 pg/ml in controls to 40.0 +/- 6.7 pg/ml at Day 1, declining to 5.3 +/- 1.1 pg/ml at Day 14. Correlated with the ET response in BALF was a considerable increase in total cell count (r = 0.61), eosinophils (r = 0.83), and neutrophils (r = 0.81). Plasma ET was not elevated. Immunohistochemical analyses revealed ET-like staining in the bronchial epithelium. Treatment with the ET receptor antagonist bosentan inhibited the increase in eosinophils in BALF and reduced the inflammatory reaction in the lung tissue. In summary, a considerable increase in the ET concentration in BALF was demonstrated during the acute phase of an experimental eosinophilic airway inflammation, coinciding with an increased ET-like immunostaining in the bronchial epithelium. Treatment with an ET receptor antagonist inhibited the inflammatory response in BALF and in the tissue.

Recently, we have shown a substantial increase in the endothelin-1 (ET-1) concentration in bronchoalveolar fluid (BALF) during an experimental eosinophilic airway inflammation. Moreover, we observed a significant inhibition of the inflammatory response after treatment with an endothelin receptor antagonist. This indicates that ET-1 may have proinflammatory properties and play a key role in eosinophilic inflammations, such as bronchial asthma. Accordingly, we hypothesized that the synthesis and release of ET-1 precedes the inflammatory response, and that the bronchial epithelium is the site of ET-1 synthesis in the lungs. An eosinophilic airway inflammation was induced by intratracheal Sephadex instillation in rats, and the animals were evaluated after 15 min, 30 min, 1, 2, 3, 6, 12, and 48 h. The ET-1 mRNA synthesis, assessed by Northern and slot blot analyses, was significantly increased 15 min after Sephadex challenge, peaking at 30 min with a 4.7-fold increase, before any signs of inflammation in the BALF could be observed. The increased synthesis was mainly located to the bronchial epithelium and macrophages at sites of inflammation as determined by in situ hybridization. A significant increase in tissue ET-1 was observed 3 h after provocation, and the recruitment of eosinophils followed a substantial release of ET-1 peptide in BALF peaking at 24 h with a 13-fold increase. Therefore, the rapid ET-1 mRNA synthesis and the considerable increase in the level of ET-1 indicate that this peptide plays an important role in the initiation of an eosinophilic airway inflammation.

Endothelin (ET)-1 has been launched as an important mediator in bronchial asthma, 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 mediators and 2) whether ET-1 stimulates the production of these mediators within the airways. These hypotheses were studied during the development of an eosinophilic airway inflammation in rats. The increase in ET-1 mRNA level in lung tissue preceded the increase in mRNA levels of tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-8. Treatment of the animals with the ET receptor antagonist bosentan resulted in a substantial decrease in the concentrations of tumor necrosis factor-alpha, IL-4, IL-1beta, interferon-gamma, and ET-1 in bronchoalveolar lavage fluid. In conclusion, the synthesis of ET-1 as measured by increased mRNA level precedes the synthesis of other proinflammatory cytokines of importance for the development of an eosinophilic airway inflammation, and ET antagonism inhibits the production of 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.