Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Physiol Rep. 2022 Oct;10(19):e15482. doi: 10.14814/phy2.15482.
Serotonin (5-hydroxytryptamine, 5-HT) is a potent pulmonary vasoconstrictor and contributes to high pulmonary vascular resistance in the developing ovine lung. In experimental pulmonary hypertension (PH), pulmonary expression of tryptophan hydroxylase-1 (TPH1), the rate limiting enzyme in 5-HT synthesis, and plasma 5-HT are increased. 5-HT blockade increases pulmonary blood flow and prevents pulmonary vascular remodeling and PH in neonatal models of PH with bronchopulmonary dysplasia (BPD). We hypothesized that neonatal tph1 knock-out (KO) mice would be protected from hypoxia-induced alveolar simplification, decreased vessel density, and PH. Newborn wild-type (WT) and tph1 KO mice were exposed to normoxia or hypoxia for 2 weeks. Normoxic WT and KO mice exhibited similar alveolar development, pulmonary vascular density, right ventricular systolic pressures (RVSPs), and right heart size. Circulating (plasma and platelet) 5-HT decreased in both hypoxia-exposed WT and KO mice. Tph1 KO mice were not protected from hypoxia-induced alveolar simplification, decreased pulmonary vascular density, or right ventricular hypertrophy, but displayed attenuation to hypoxia-induced RVSP elevation compared with WT mice. Tph1 KO neonatal mice are not protected against hypoxia-induced alveolar simplification, reduction in pulmonary vessel density, or RVH. While genetic and pharmacologic inhibition of tph1 has protective effects in adult models of PH, our results suggest that tph1 inhibition would not be beneficial in neonates with PH associated with BPD.
5-羟色胺（5-HT）是一种有效的肺血管收缩剂，在发育中的羊肺中导致高肺血管阻力。在实验性肺动脉高压（PH）中，5-HT 合成的限速酶色氨酸羟化酶-1（TPH1）的肺表达和血浆 5-HT 增加。5-HT 阻断可增加肺血流量，并预防伴有支气管肺发育不良（BPD）的新生儿 PH 模型中的肺血管重塑和 PH。我们假设，新生 tph1 敲除（KO）小鼠将免受缺氧引起的肺泡简化、血管密度降低和 PH 的影响。新生野生型（WT）和 tph1 KO 小鼠分别暴露于常氧或缺氧 2 周。常氧 WT 和 KO 小鼠表现出相似的肺泡发育、肺血管密度、右心室收缩压（RVSP）和右心大小。在缺氧暴露的 WT 和 KO 小鼠中，循环（血浆和血小板）5-HT 均降低。与 WT 小鼠相比，tph1 KO 小鼠并未免受缺氧引起的肺泡简化、肺血管密度降低或右心室肥大的影响，但对缺氧引起的 RVSP 升高的反应减弱。tph1 KO 新生小鼠不能防止与 BPD 相关的 PH 引起的肺泡简化、肺血管密度降低或 RVH。虽然 tph1 的遗传和药理学抑制在成人 PH 模型中具有保护作用，但我们的结果表明，tph1 抑制在伴有 BPD 的 PH 的新生儿中可能没有益处。
