Serotonin 2A receptor inhibition protects against the development of pulmonary hypertension and pulmonary vascular remodeling in neonatal mice
Serotonin 2A receptor inhibition protects against the development of pulmonary hypertension and pulmonary vascular remodeling in neonatal mice
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DOI：
10.1152/ajplung.00215.2017
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发表时间：
2018-05-01
影响因子：
4.9
通讯作者：
Nozik-Grayck, Eva
中科院分区：
文献类型：
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作者：
Delaney, Cassidy;Sherlock, Laurie;Nozik-Grayck, Eva
肺动脉高压（PH）合并支气管肺发育不良（BPD）影响早产儿的临床结局。血清素（5-羟色胺，5-HT）信号传导增加在成人PH发病机制和进展中起着重要作用。我们推测5-HT信号增加有助于新生儿PH的发病机制，并发BPD和新生儿肺损伤。因此，我们研究了5-HT信号在新生小鼠暴露于博莱霉素，以前证明诱导PH和肺泡简化。新生野生型小鼠接受腹膜内PBS、酮色林（lmg/kg）、博来霉素（3U/kg）或博来霉素（3U/kg）加酮色林（lmg/kg）每周三次，持续3周。博莱霉素治疗后，肺表达的5-羟色胺合成的限速酶，色氨酸羟化酶-1（Tph 1），显着增加。博莱霉素不影响肺5-HT 2A受体（R）的表达，但增加肺5-HT 2BR和5-羟色胺转运体的基因表达。酮色林治疗可减轻博莱霉素诱导的PH（RVSP和RVH增加）和肺血管重塑（血管密度降低和小血管肌化增加）。此外，我们发现，酮色林治疗激活肺MAPK和Akt信号在小鼠暴露于博莱霉素。我们的结论是，5-HT信号增加，在新生儿肺高压和药理学抑制5-HT 2AR的小鼠模型保护对新生儿肺损伤的PH的发展。我们推测这是通过恢复MAPK信号和增加Akt信号而发生的。
Pulmonary hypertension (PH) complicating bronchopulmonary dysplasia (BPD) worsens clinical outcomes in former preterm infants. Increased serotonin (5-hydroxytryptamine, 5-HT) signaling plays a prominent role in PH pathogenesis and progression in adults. We hypothesized that increased 5-HT signaling contributes to the pathogenesis of neonatal PH, complicating BPD and neonatal lung injury. Thus, we investigated 5-HT signaling in neonatal mice exposed to bleomycin, previously demonstrated to induce PH and alveolar simplification. Newborn wild-type mice received intraperitoneal PBS, ketanserin (1 mg/kg), bleomycin (3 U/kg) or bleomycin (3 U/kg) plus ketanserin (1 mg/kg) three times weekly for 3 wk. Following treatment with bleomycin, pulmonary expression of the rate-limiting enzyme of 5-HT synthesis, tryptophan hydroxylase-1 (Tph1), was significantly increased. Bleomycin did not affect pulmonary 5-HT 2A receptor (R) expression, but did increase pulmonary gene expression of the 5-HT 2BR and serotonin transporter. Treatment with ketanserin attenuated bleomycin-induced PH (increased RVSP and RVH) and pulmonary vascular remodeling (decreased vessel density and increased muscularization of small vessels). In addition, we found that treatment with ketanserin activated pulmonary MAPK and Akt signaling in mice exposed to bleomycin. We conclude that 5-HT signaling is increased in a murine model of neonatal PH and pharmacological inhibition of the 5-HT 2AR protects against the development of PH in neonatal lung injury. We speculate this occurs through restoration of MAPK signaling and increased Akt signaling.