Delayed thromboxane or tumor necrosis factor-α, but not leukotriene inhibition, attenuates prolonged pulmonary hypertension in endotoxemia

Academic Article

Abstract

  • The early phase of endotoxin-induced acute hemodynamic disturbances and hypoxemia is mediated by various factors, including eicosanoids and tumor necrosis factor-α (TNF(α)). Thromboxane A2 is the major mediator of the early pulmonary hypertension associated with endotoxemia, but the mechanisms underlying the prolonged hemodynamic disturbances observed in ongoing endotoxemia are not well understood. The authors used a chronically instrumented young piglet model to determine the roles of several eicosanoids and of TNF(α) in the prolonged endotoxin-induced pulmonary hypertension and other cardiovascular derangements. Animals were given 40 μg/kg endotoxin intravenously per hour for 30 minutes, followed by 20 μg/kg per hour. In all animals, persistent pulmonary hypertension, lowered cardiac output, and hypoxemia developed during endotoxin infusion. After 3 hours of endotoxin infusion, randomly ordered infusions of 1 mg/kg dazmegrel (a thromboxane A2 synthesis inhibitor), 5 mg/kg nordihydroguaiaretic acid (a 5-1ipoxygenase inhibitor), and 20 mg/kg pentoxifylline (a TNF(α) inhibitor) were given intravenously at 30- to 60minute intervals. Dazmegrel and pentoxifylline lowered pulmonary arterial pressure and resistance and raised arterial oxygen tension. Cardiac output increased significantly after pentoxifylline. These hemodynamic effects persisted for 30-60 minutes, despite continued endotoxin infusion. The elevated plasma concentrations ofthromboxane B2 and TNF(α) returned toward preendotoxin baseline values after dazmegrel and pentoxifylline treatment, respectively. No beneficial effects were noted after administration of nordihydroguaiaretic acid. Based on these results, both thromboxane A2 and TNF(α), but not 5-lipoxygenase products, play active roles in prolonged endotoxin-induced pulmonary hypertension and hypoxemia in young piglets. Combined thromboxane A2 and TNF(α) blockade may be clinically useful in treatment of advanced sepsis in neonates.
  • Digital Object Identifier (doi)

    Author List

  • Li JX; Oliver JR; Lu CY; Philips JB
  • Start Page

  • 103
  • End Page

  • 110
  • Volume

  • 310
  • Issue

  • 3