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

Objectives: Recent studies have indicated effectiveness of glucocorticoid ( GC) treatment in late, fibroproIiferative adult respiratory distress syndro me. There is furthermore growing evidence for a role of endothelin-1 (ET-1) in lung fibroproliferation, but the impact of GC on stimulated pulmonary E T-1 is not well defined. Design and setting: Prospective study in an experimental laboratory Subjects: Male Wistar rats. Interventions: Isolated lungs were perfused over 120 min in recirculatory m ode in presence of vehicle, interleukin-1 beta (IL-1 beta; 5 ng/ml) plus tu mor necrosis factor-a (TNF-a; 5 ng/ml), dexamethasone (Dx; 1 nmol/l), Dx (1 0 nmol/l), IL-1 beta plus TNF alpha plus Dx; I, or IL-1 beta plus TNFa plus Ex 10 (n = 6 each). Pulmonary artery endothelial cells were stimulated ove r 30 min using a similar protocol. Measurements and results: 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 inc reased release of big ET-1 and ET-1, to 220 % and 217 %, and lung content o f 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 nucl ear extracts of pulmonary arteely endothelial cells demonstrated nuclear bi nding of the transcription factor nuclear factor kappa B in response to 1 b eta plus TNF-alpha, which was decreased in presence of Dx 1 and Dx 10. Conclusions: GC inhibit the cytokine-induced upregulation of pulmonary vasc ular and tissue endothelins, possibly via nuclear factor kappaB dependent m echanisms. This finding may reinforce the therapeutic employment of GC in l ate ARDS.