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Physiol Rep ; 4(12)2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27354543

RESUMEN

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.


Asunto(s)
Hiperoxia/metabolismo , Hipoxia/metabolismo , Miocitos del Músculo Liso/metabolismo , Terapia por Inhalación de Oxígeno/efectos adversos , Síndrome de Circulación Fetal Persistente/metabolismo , Glicoproteínas de Membrana Plaquetaria/metabolismo , Arteria Pulmonar/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , AMP Cíclico/metabolismo , Síndrome de Circulación Fetal Persistente/fisiopatología , Síndrome de Circulación Fetal Persistente/terapia , Unión Proteica , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Arteria Pulmonar/citología , Ovinos , Transducción de Señal , Vasoconstricción
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