ABSTRACT: The endogenously produced cytokine, tumor necrosis factor-α (TNF-α), has been shown in adult animal models to be associated with many of the pathophysiologic effects of sepsis, including systemic hypotension and hemorrhagic necrosis. TNF-α can induce the release of various vasoactive arachidonic acid metabolites, suggesting that TNF-α may act either directly or via intermediary substances in producing its effects. The pathophysiologic role of TNF-α in neonatal sepsis, especially its potential effect on pulmonary vascular tone, is presently unknown. To assess the role of TNF-α in neonatal sepsis, 19 piglets (19 ± 5 d old) were anesthetized, intubated, paralyzed, mechanically ventilated, and catheterized to assess pulmonary and systemic vascular hemodynamics and pulmonary gas exchange. The multiple inert gas elimination technique was used to assess ventilation perfusion matching. A 30-min infusion of human recombinant TNF-α (250 μg/kg total dose) was administered to animals pretreated with either 10 mg/kg dazmegrel, a thromboxane synthase inhibitor (n = 9) or placebo (n = 10). TNF-α alone induced a prompt and sustained rise in pulmonary arterial pressure and pulmonary vascular resistance that continued at least for 2 h after onset of the infusion. In contrast, the animals pretreated with dazmegrel demonstrated no rise in pulmonary vascular resistance until 2 h after the onset of the infusion. Neither group of animals demonstrated a significant decline in arterial or evidence from inert gas analysis of VA/Q mismatching or increase in intrapulmonary shunt. We conclude that human recombinant TNF-α induces an acute and sustained elevation in Ppa and PVR without the concomitant development of hypoxemia or intrapulmonary shunt. The pulmonary hypertension is blocked acutely by the putative TxA2 synthase inhibitor, dazmegrel.
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Truog, W., Gibson, R., Henderson, W. et al. Tumor Necrosis Factor-Induced Neonatal Pulmonary Hypertension: Effects of Dazmegrel Pretreatment. Pediatr Res 27, 466–471 (1990) doi:10.1203/00006450-199005000-00010
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