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


METHODS
Prospective study in an experimental laboratory.


METHODS
Male Wistar rats.


METHODS
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.


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 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.


CONCLUSIONS
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.
Dschietzig
T
T
Medizinische Klinik und Poliklinik I (Kardiologie), Charité, Humboldt-Universität zu Berlin, Schumannstrasse 20/21, 10098 Berlin, Germany.
Richter
C
C
Pfannenschmidt
G
G
Bartsch
C
C
Laule
M
M
Baumann
G
G
Stangl
K
K
D000818:Animals; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D011446:Prospective Studies; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012128:Respiratory Distress Syndrome / Q000378:metabolism*
D016207:Cytokines; D019332:Endothelin-1; D005938:Glucocorticoids; D016328:NF-kappa B; D003907:Dexamethasone