Renteria L S, Cruz E, Ibe B O
Division of Neonatology, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA.
J Dev Orig Health Dis. 2013 Dec;4(6):458-69. doi: 10.1017/S2040174413000366.
Platelet-activating factor (PAF) is a phospholipid with a wide range of biological activities. We studied PAF metabolism and PAF receptor (PAFR) signaling in perinatal ovine lungs to understand PAF's role in transition of the perinatal pulmonary hemodynamics and pathophysiology of persistent pulmonary hypertension of the newborn. We hypothesized that downregulation of PAF synthesis with upregulation of PAF catabolism by acetylhydrolase (PAF-Ah) in the newborn lung is needed for fetus-to-newborn pulmonary adaptation. Studies were conducted on fetal and newborn lamb pulmonary arteries (PA), veins (PV) and smooth muscle cells (SMC). PAF metabolism, PAFR binding and cell proliferation were studied by cell culture; gene expression was studied by qPCR. Fetal lungs synthesized 60% more PAF than newborn lungs. Compared with the fetal PVs and SMCs, PAF-Ah activity in newborn was 40-60% greater. PAF-Ah mRNA expression in newborn vessels was different from the expression by fetal PA. PAF-Ah gene clone activity confirmed deletion of hypoxia-sensitive site. PAFR mRNA expression by the PVs and SMC-PV of the fetus and newborn was greater than by corresponding PAs and SMC-PA. Q-PCR study of PAFR expression by the SMC-PV of both groups was greater than SMC-PA. Fetal SMCs bound more PAF than the newborn SMCs. PAFR antagonist, CV-3988, inhibited PAFR binding and DNA synthesis by the fetal SMCs, but augmented binding and DNA synthesis by newborn cells. We show different PAF-PAFR mediated effects in perinatal lungs, suggesting both transcriptional and translational regulation of PAF-Ah and PAFR expression in the perinatal lamb lungs. These indicate that the downregulation of PAF-mediated effects postnatally protects against persistent pulmonary hypertension of the newborn.
血小板活化因子（PAF）是一种具有广泛生物活性的磷脂。我们研究了围产期绵羊肺中PAF的代谢和PAF受体（PAFR）信号传导，以了解PAF在围产期肺血流动力学转变及新生儿持续性肺动脉高压病理生理学中的作用。我们假设，新生儿肺中PAF合成的下调以及乙酰水解酶（PAF-Ah）介导的PAF分解代谢的上调是胎儿向新生儿肺适应所必需的。我们对胎羊和新生羊的肺动脉（PA）、静脉（PV）和平滑肌细胞（SMC）进行了研究。通过细胞培养研究PAF代谢、PAFR结合和细胞增殖；通过定量聚合酶链反应（qPCR）研究基因表达。胎肺合成的PAF比新生肺多60%。与胎儿PV和SMC相比，新生儿的PAF-Ah活性高40%-60%。新生儿血管中PAF-Ah mRNA表达与胎儿PA中的表达不同。PAF-Ah基因克隆活性证实缺氧敏感位点缺失。胎儿和新生儿PV及SMC-PV中PAFR mRNA表达高于相应的PA及SMC-PA。两组SMC-PV中PAFR表达的qPCR研究结果显示，其表达量高于SMC-PA。胎儿SMC比新生SMC结合更多的PAF。PAFR拮抗剂CV-3988抑制胎儿SMC的PAFR结合和DNA合成，但增强新生细胞的结合和DNA合成。我们展示了围产期肺中PAF-PAFR介导的不同效应，提示围产期羔羊肺中PAF-Ah和PAFR表达存在转录和翻译调控。这些结果表明，出生后PAF介导效应的下调可预防新生儿持续性肺动脉高压。
