Stimulation of pulmonary big endothelin-1 and endothelin-1 by antithrombinIII: A rationale for combined application of antithrombin III and endothelin antagonists in sepsis-related acute respiratory distress syndrome?

Objectives: Antithrombin (AT) III reduces lung damage in animal models of s eptic acute respiratory distress syndrome (ARDS), which is generally attrib uted to stimulation of endothelial prostacyclin synthesis. However, clinica l studies have failed so far to demonstrate mortality reduction by applicat ion of AT III. We investigated whether AT III stimulates pulmonary prostacy clin release. In addition, we hypothesized that it may promote pulmonary en dothelins, thereby mitigating its own protective effect in the course of AR DS. Design: Controlled experiment using isolated organs. Setting: Experimental laboratory. Subjects: Male Wistar rats. Interventions Isolated lungs were perfused over 120 mins in recirculatory m ode in the presence of 50 mu g/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 vascu lar release of thromboxane 82, 6-keto-prostaglandin-F1 alpha, big endotheli n-1, and endothelin-1. Control lungs released 59 +/- 23 pg/mL thromboxane B 2, 1480 +/- 364 pg/mL 6-keto-prostaglandin-F1 alpha, 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-F1 alpha re lease 1.6-fold, and endothelin-1 1.6-fold (p < .05 each); levels of big end othelin-1 were unchanged. AT III at 2 U/mL elevated production of big endot helin-1 (1.7-fold) and endothelin-1 (1.2-fold) (p < .05 for both). AT III a t 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-F1 alpha concentrations. Application of 2 U/mL AT III plus endotoxin stimulated big endothelin- production1 (2.6-fold) compar ed with endotoxin or AT III alone (p < .05 for both), but did not further e zdslevate 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, par ticularly, under septic conditions, which may blunt the AT Ill-induced lung protection during ARDS, Therefore, we suggest combined application of AT H I and endothelin antagonists in animal models of septic ARDS.