Cyclic nucleotides down regulate PAF receptor mediated effects in newborn ovine pulmonary arterial smooth muscle: significance in oxygen therapy of persistent pulmonary hypertension of the newborn (LB605)

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Platelet activating factor (PAF) is implicated in the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN). Baseline PAFr activity is higher in fetal ovine pulmonary artery smooth muscle cells (PASMC) and is augmented by hypoxia. In fetal PASMC we have shown evidence of crosstalk between PAFr‐mediated cell signaling and activity of cyclic nucleotides (Cnucs) via respective receptors PKG and PKA. Since these mechanisms are not well described in the newborn counterpart, we studied effects of Cnucs on PAFr protein expression in newborn PASMC. Because long term effects of oxygen therapy on newborn lung are not well understood, we included various oxygen tension study conditions. We hypothesize that PPHN results from failure of newborn lamb pulmonary system to down regulate PAFr activity or to up regulate vasodilatory Cnuc activity.PASMC harvested from ovine newborns 6‐12d old were incubated for 24h with culture media or media containing 10μM cGMP or cAMP analogs or 0.1μM of PAF in normoxia (pO2~100torr), hypoxia (pO2 <40 torr) and hyperoxia (5% CO2, O2). Prostacyclin and TxA2 release were measured and compared to release by fetal PASMC. Proliferation studies were performed under the three conditions and PAFr, PKA and PKG expression were measured.Newborn PA baseline prostacyclin level was 9‐fold greater than in fetal PA, whereas baseline production of TxA2 by newborn PA was 7‐fold less. Overall, 24h hyperoxia attenuated cell proliferation across all treatments. Cnuc treatment attenuated PAF stimulation of proliferation and decreased PAFr expression.Elevated prostacyclin production over TxA2 suggests greater cyclooxygenase activity in newborn PA postnatally. Down regulation of PAFr effects by Cnucs indicates that normal newborn PA physiology favors vasodilatory pathways to minimize PAF‐induced hypertrophy or hyperplasia. Thus failure of newborn lung to anchor down regulation of vasoconstrictors with up regulation of vasodilators leads to pathogenesis of PPHN.