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 A 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 A 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 B 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 A and TNF(α), but not 5-lipoxygenase products, play active roles in prolonged endotoxin-induced pulmonary hypertension and hypoxemia in young piglets. Combined thromboxane A and TNF(α) blockade may be clinically useful in treatment of advanced sepsis in neonates. 2 2 2 2 2
  • Digital Object Identifier (doi)

    Author List

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

  • 103
  • End Page

  • 110
  • Volume

  • 310
  • Issue

  • 3