DELAYED THROMBOXANE OR TUMOR-NECROSIS-FACTOR-ALPHA, BUT NOT LEUKOTRIENE INHIBITION, ATTENUATES PROLONGED PULMONARY-HYPERTENSION IN ENDOTOXEMIA

The early phase of endotoxin-induced acute hemodynamic disturbances an d hypoxemia is mediated by various factors, including eicosanoids and tumor necrosis factor-alpha (TNFalpha). Thromboxane A(2) is the major mediator of the early pulmonary hypertension associated with endotoxem ia, but the mechanisms underlying the prolonged hemodynamic disturbanc es observed in ongoing endotoxemia are not well understood. The author s used a chronically instrumented young piglet model to determine the roles of several eicosanoids and of TNFalpha in the prolonged endotoxi n-induced pulmonary hypertension and other cardiovascular derangements . Animals were given 40 mu g/kg endotoxin intravenously per hour for 3 0 minutes, followed by 20 mu g/kg per hour. In all animals, persistent pulmonary hypertension, lowered cardiac output, and hypoxemia develop ed during endotoxin infusion. After 3 hours of endotoxin infusion, ran domly ordered infusions of 1 mg/kg dazmegrel (a thromboxane A(2) synth esis inhibitor), 5 mg/kg nordihydroguaiaretic acid (a 5-lipoxygenase i nhibitor), and 20 mg/kg pentoxifylline (a TNFalpha inhibitor) were giv en intravenously at 30- to 60-minute intervals. Dazmegrel and pentoxif ylline lowered pulmonary arterial pressure and resistance and raised a rterial oxygen tension. Cardiac output increased significantly after p entoxifylline. These hemodynamic effects persisted for 30-60 minutes, despite continued endotoxin infusion. The elevated plasma concentratio ns of thromboxane B-2 and TNFalpha returned toward pre-endotoxin basel ine values after dazmegrel and pentoxifylline treatment, respectively. No beneficial effects were noted after administration of nordihydrogu aiaretic acid. Based on these results, both thromboxane A(2) and TNFal pha, but not 5-lipoxygenase products, play active roles in prolonged e ndotoxin-induced pulmonary hypertension and hypoxemia in young piglets . Combined thromboxane A(2) and TNFalpha blockade may be clinically us eful in treatment of advanced sepsis in neonates.