Stimulation of pulmonary big endothelin-1 and endothelin-1 by antithrombin III: a rationale for combined application of antithrombin III and endothelin antagonists in sepsis-related acute respiratory distress syndrome?
OBJECTIVE
Antithrombin (AT) III reduces lung damage in animal models of septic acute respiratory distress syndrome (ARDS), which is generally attributed to stimulation of endothelial prostacyclin synthesis. However, clinical studies have failed so far to demonstrate mortality reduction by application of AT III. We investigated whether AT III stimulates pulmonary prostacyclin release. In addition, we hypothesized that it may promote pulmonary endothelins, thereby mitigating its own protective effect in the course of ARDS.


METHODS
Controlled experiment using isolated organs.


METHODS
Experimental laboratory.


METHODS
Male Wistar rats.


METHODS
Isolated lungs were perfused over 120 mins in recirculatory mode in the presence of 50 microg/mL endotoxin (n = 11), 2U/mL AT III (n = 10), 5 U/mL AT III (n = 13), endotoxin plus 2 U/mL AT III (n = 5), or vehicle alone (controls, n = 13), respectively.


RESULTS
We determined the effects of AT III on vascular release of thromboxane B2, 6-keto-prostaglandin-F1alpha, big endothelin-1, and endothelin-1. Control lungs released 59+/-23 pg/mL thromboxane B2, 1,480+/-364 pg/mL 6-keto-prostaglandin-F1alpha, 15.2+/-4.5 pg/mL big endothelin-1, and 0.46+/-0.13 pg/mL endothelin-1. Exposure to endotoxin increased thromboxane B2 release 2.9-fold, 6-keto-prostaglandin-F1alpha release 1.6-fold, and endothelin-1 1.6-fold (p < .05 each); levels of big endothelin-1 were unchanged. AT III at 2 U/mL elevated production of big endothelin-1 (1.7-fold) and endothelin-1 (1.2-fold) (p < .05 for both). AT III at 5 U/mL enhanced levels of big endothelin-1 (1.6-fold) and endothelin-1 (1.3-fold) (p < .05 for both). Neither dose of AT III affected thromboxane B2 or 6-keto-prostaglandin-F1alpha concentrations. Application of 2 U/mL AT III plus endotoxin stimulated big endothelin-1 production (2.6-fold) compared with endotoxin or AT III alone (p < .05 for both), but did not further elevate endothelin-1 release.


CONCLUSIONS
AT III does not stimulate pulmonary prostacyclin, but promotes pulmonary release of big endothelin-1 and endothelin-1 under basal and, particularly, under septic conditions, which may blunt the AT III-induced lung protection during ARDS. Therefore, we suggest combined application of AT III and endothelin antagonists in animal models of septic ARDS.
Medizinische Klinik und Poliklinik I, Charité, Humboldt-Universität zu Berlin, Germany.
T
T
Dschietzig
K
K
Alexiou
M
M
Laule
R
R
Becker
K
K
Schrör
G
G
Baumann
F
F
Brunner
K
K
Stangl
D000704:Analysis of Variance; D000818:Animals; D000990:Antithrombin III / Q000627:therapeutic use*; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004731:Endotoxins / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D013929:Thromboxane B2 / Q000378:metabolism
D019332:Endothelin-1; D004731:Endotoxins; D015842:Serine Proteinase Inhibitors; D013929:Thromboxane B2; D000990:Antithrombin III; D011464:Epoprostenol