Endothelin production and effects of endothelin antagonism during experimental airway inflammation.
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.
Finsnes
F
F
Department of Pulmonary Medicine, University of Oslo, Ulleval Hospital, Norway.
Skjønsberg
O H
OH
Tønnessen
T
T
Naess
O
O
Lyberg
T
T
Christensen
G
G
D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D000077300:Bosentan; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D003911:Dextrans; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects; D005782:Gels; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000627:therapeutic use*
D003911:Dextrans; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D005782:Gels; D013449:Sulfonamides; C025614:sephadex; D000077300:Bosentan