Deficiency in ST2 signaling ameliorates RSV-associated pulmonary hypertension.
Deficiency in ST2 signaling ameliorates RSV-associated pulmonary hypertension.
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ST2 信号传导缺陷可改善 RSV 相关的肺动脉高压。
DOI：
10.1152/ajpheart.00018.2021
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Kimura,Dai
中科院分区：
文献类型：
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作者：
Vu,LuanD;Saravia,Jordy;Jaligama,Sridhar;BaboeramPanday,RajshriV;Sullivan,RyanD;Mancarella,Salvatore;Cormier,StephaniaA;Kimura,Dai
在呼吸道合胞病毒（RSV）细支气管炎期间观察到的肺动脉高压（PH）与发病率和死亡率相关，尤其是在患有先天性心脏病的儿童中。然而，RSV相关PH的病理生理机制仍不清楚。因此，本研究旨在探讨RSV相关PH的病理生理机制。我们使用了RSV相关PH的转译小鼠模型，其中野生型（WT）和致瘤性抑制2（ST 2）基因敲除的新生小鼠在5日龄时感染RSV，4周后再感染。RSV再感染后WT小鼠中PH的发展表现为右心室收缩压升高、肺动脉加速时间（PAT）缩短和PAT/射血时间（ET）比值降低。这与骨膜蛋白和IL-13表达的增加以及由过氧化物酶1和2引起的过氧化物酶生物活性的增加以及一氧化氮合酶（NOS）解偶联的诱导相一致。ST 2信号的缺乏通过抑制NOS解偶联来防止RSV再感染小鼠发生PH。总之，ST 2信号参与RSV相关PH的发展。ST 2信号抑制可能是RSV相关PH的新的治疗靶点。新&值得注意的是，我们报告了ST 2介导的2型免疫和机制的致病作用有助于RSV相关肺动脉高压。抑制ST 2信号传导可能是这种疾病的新的治疗靶点。
Pulmonary hypertension (PH) observed during respiratory syncytial virus (RSV) bronchiolitis is associated with morbidity and mortality, especially in children with congenital heart disease. Yet, the pathophysiological mechanisms of RSV-associated PH remain unclear. Therefore, this study aimed to investigate the pathophysiological mechanism of RSV-associated PH. We used a translational mouse model of RSV-associated PH, in which wild-type (WT) and suppression of tumorigenicity 2 (ST2) knockout neonatal mice were infected with RSV at 5 days old and reinfected 4 wk later. The development of PH in WT mice following RSV reinfection was evidenced by elevated right ventricle systolic pressure, shortened pulmonary artery acceleration time (PAT), and decreased PAT/ejection time (ET) ratio. It coincided with the augmentation of periostin and IL-13 expression and increased arginase bioactivity by both arginase 1 and 2 as well as induction of nitric oxide synthase (NOS) uncoupling. Absence of ST2 signaling prevented RSV-reinfected mice from developing PH by suppressing NOS uncoupling. In summary, ST2 signaling was involved in the development of RSV-associated PH. ST2 signaling inhibition may be a novel therapeutic target for RSV-associated PH.NEW & NOTEWORTHYWe report that the pathogenic role of ST2-mediated type 2 immunity and mechanisms contribute to RSV-associated pulmonary hypertension. Inhibiting ST2 signaling may be a novel therapeutic target for this condition.