title: Hypoxia and hyperoxia potentiate PAF receptor-mediated effects in newborn ovine pulmonary arterial smooth muscle cells: significance in oxygen therapy of PPHN.
abstract: Platelet-activating factor (PAF) acting via its receptor (PAFR) is implicated in the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN). Effects of long-term oxygen therapy on newborn lung are not well understood; therefore, we studied the effect of oxygen tension on ovine newborn pulmonary artery smooth muscle cells (NBPASMC). Our global hypothesis is that PPHN results from failure of newborn lamb pulmonary system to downregulate PAFR activity or to upregulate vasodilatory cyclic nucleotides (Cnucs) activity. NBPASMC from newborns 6-12 days old were studied in vitro at three different oxygen tensions (pO2, [Torr]: hypoxia, <40; normoxia, 80-100; and hyperoxia, >100 Torr often clinically imposed upon newborns with PPHN) PAFR- and Cnucs mediated effects were determined. PAFR and PKA Cα mRNA expression as well as prostacyclin, thromboxane, cAMP production, and DNA synthesis was studied to assess PAFR-mediated hypertrophy and/or hyperplasia. Hypoxia and hyperoxia increased specific PAFR binding. PAF treatment during hyperoxia increased PAFR gene, but decreased PKA-Cα gene expression. Hypoxia and hyperoxia increased NBPASMC proliferation via PAFR signaling. Baseline prostacyclin level was ninefold greater than in fetal PASMC, whereas baseline thromboxane was sevenfold less suggesting greater postnatal cyclooxygenase activity in NBPASMC PAF decreased, while forskolin and 8-Br-cAMP increased cAMP production. Decrease of PAFR effects by Cnucs indicates that normal newborn PA physiology favors vasodilator pathways to minimize PAF-induced hypertrophy or hyperplasia. We speculate that failure of newborn lung to anchor downregulation of vasoconstrictors with upregulation of vasodilators leads to PPHN.
authors.affiliation: Division of Neonatology, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.
authors.forename: Mona
authors.initials: M
authors.lastname: Hanouni
authors.affiliation: Division of Neonatology, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Bernal
authors.affiliation: Division of Neonatology, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.
authors.forename: Shaemion
authors.initials: S
authors.lastname: McBride
authors.affiliation: Division of Neonatology, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.
authors.forename: Vincent Reginald F
authors.initials: VR
authors.lastname: Narvaez
authors.affiliation: Division of Neonatology, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California ibe@labiomed.org.
authors.forename: Basil O
authors.initials: BO
authors.lastname: Ibe
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010102:Oxygen Inhalation Therapy / Q000009:adverse effects*; D010547:Persistent Fetal Circulation Syndrome / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012756:Sheep; D015398:Signal Transduction; D014661:Vasoconstriction
chemical_list: D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D000242:Cyclic AMP; D011493:Protein Kinase C
keywords: PAF receptor; PKA; cAMP; hyperoxia; prostacyclin