Thromboxane A2 receptors mediate pulmonary hypertension in 60% oxygen-exposed newborn rats by a cyclooxygenase-independent mechanism

Robert P. Jankov, Rosetta Belcastro, Emira Ovcina, Julia Lee, Hamid Massaeli, Stephen J. Lye, A. Keith Tanswell

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45 Citations (Scopus)

Abstract

Endothelin-1 (ET-1) mediates the development of pulmonary hypertension (PHT) in newborn rats exposed to 60% O2 for 14 days, a model for human chronic neonatal lung iniury. ET-1 production by d-14 rat pulmonary artery smooth muscle cells in vitro was markedly increased by thromboxane (TX) A2 receptor agonists and inhibited by a competitive antagonist. We hypothesized that stimulation of the TX A2 receptor contributed to O2-mediated PHT in vivo. Newborn rat pups received daily intraperitoneal injections of L670596, a competitive TX A2 receptor antagonist, or 5,5-dimethyl-3-(3-fluorophenyl)4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a cyclooxygenase-2 inhibitor, during 14 days of 60% O2 or air exposure. L670596, but not DFU, prevented 60% O2-mediated right ventricular and small pulmonary vessel smooth muscle hypertrophy. Lung ET-1 content was significantly reduced by L670596 in 60% O2-exposed animals. We conclude that TX A2 receptor activation, though not by TX A2, caused upregulation of ET-1 and PHT in this model. A likely mediator is the stable lipid peroxidation product, 8-iso-prostane, which acts as an incidental ligand of the TX A2 receptor and is a potent inducer of ET-1 production by cultured d-14 rat pulmonary artery smooth muscle cells in vitro.

Original languageEnglish
Pages (from-to)208-214
Number of pages7
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume166
Issue number2
DOIs
Publication statusPublished - 15 Jul 2002

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Keywords

  • 8-isoprostane
  • Endothelin-1
  • Pulmonary oxygen toxicity
  • Reactive oxygen species

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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