Dexamethasone inhibits stimulation of pulmonary endothelins by proinflammatory cytokines: possible involvement of a nuclear factor kappa B dependent mechanism.

Abstract

Recent studies have indicated effectiveness of glucocorticoid (GC) treatment in late, fibroproliferative adult respiratory distress syndrome. There is furthermore growing evidence for a role of endothelin-1 (ET-1) in lung fibroproliferation, but the impact of GC on stimulated pulmonary ET-1 is not well defined. Prospective study in an experimental laboratory. Male Wistar rats. Isolated lungs were perfused over 120 min in recirculatory mode in presence of vehicle, interleukin-1 beta (IL-1 beta; 5 ng/ml) plus tumor necrosis factor-alpha (TNF-alpha; 5 ng/ml), dexamethasone (Dx; 1 nmol/l), Dx (10 nmol/l), IL-1 beta plus TNF alpha plus Dx 1, or IL-1 beta plus TNF alpha plus Dx 10 (n = 6 each). Pulmonary artery endothelial cells were stimulated over 30 min using a similar protocol. Control lungs released 15.2 +/- 0.6 pg/ml big ET-1 and 0.46 +/- 0.06 pg/ml ET-1, and contained 0.73 +/- 0.05 ng/g wet weight (ww) big ET-1 and 3.06 +/- 0.22 ng/g ww ET-1. IL-1 beta plus TNF-alpha increased release of big ET-1 and ET-1, to 220% and 217%, and lung content of peptides, to 236% and 230%. Dx dose-dependently inhibited the cytokine-induced rise in peptide release and lung content and completely suppressed these effects at 10 nmol/l. Electrophoretic mobility shift assays with nuclear extracts of pulmonary artery endothelial cells demonstrated nuclear binding of the transcription factor nuclear factor kappa B in response to IL-1 beta plus TNF-alpha, which was decreased in presence of Dx 1 and Dx 10. GC inhibit the cytokine-induced upregulation of pulmonary vascular and tissue endothelins, possibly via nuclear factor kappa B dependent mechanisms. This finding may reinforce the therapeutic employment of GC in late ARDS.