ENDOTHELIN PRODUCTION AND EFFECTS OF ENDOTHELIN ANTAGONISM DURING EXPERIMENTAL AIRWAY INFLAMMATION

Endothelin (ET) has strong bronchoconstrictor properties, stimulate mu cus secretion and mucosal edema, and may also exert proinflammatory ef fects. 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 d uring airway inflammation induced by intratracheal instillation of dex tran (Sephadex). We observed a considerable increase in the concentrat ion of ET in bronchoalveolar lavage fluid (BALF) during the early phas e 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 +/- 7.1 pg/ml at Day 14. Correlated with the ET response in BALF was a considerable increa se in total cell count (r = 0.61), eosinophils (r = 0.83), and neutrop hils (r = 0.81). Plasma ET was not elevated. Immunohistochemical analy ses revealed ET-like staining in the bronchial epithelium. Treatment w ith the ET receptor antagonist bosentan inhibited the increase in eosi nophils in BALF and reduced the inflammatory reaction in the lung tiss ue. In summary, a considerable increase in the ET concentration in BAL F was demonstrated during the acute phase of an experimental eosinophi lic airway inflammation, coinciding with an increased ET-like immunost aining in the bronchial epithelium, Treatment with an ET receptor anta gonist inhibited the inflammatory response in BALF and in the tissue.