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?

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Abstract
Objectives 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. Design Controlled experiment using isolated organs. Setting Experimental laboratory. Subjects Male Wistar rats. Interventions Isolated lungs were perfused over 120 mins in recirculatory mode in the presence of 50 μg/mL endotoxin (n = 11), 2 U/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. Measurements and Main Results We determined the effects of AT III on vascular release of thromboxane B2, 6-keto-prostaglandin-F1α, big endothelin-1, and endothelin-1. Control lungs released 59 ± 23 pg/mL thromboxane B2, 1480 ± 364 pg/mL 6-keto-prostaglandin-F1α, 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-F1α 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-F1α 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.