Department of Pediatrics, University of Tennessee Health Science Center, Children's Foundation Research Institute, Le Bonheur Children's Hospital , Memphis, Tennessee.
Department of Immunology, St. Jude Children's Research Hospital , Memphis, Tennessee.
Am J Physiol Heart Circ Physiol. 2018 Sep 1;315(3):H581-H589. doi: 10.1152/ajpheart.00627.2017. Epub 2018 Jun 15.
Pulmonary hypertension (PH) has been observed in up to 75% of infants with moderate to severe respiratory syncytial virus (RSV) bronchiolitis and is associated with significant morbidity and mortality in infants with congenital heart disease. The purpose of the present study was to establish a mouse model of PH secondary to RSV bronchiolitis that mimics the disease etiology as it occurs in infants. Neonatal mice were infected with RSV at 5 days of age and then reinfected 4 wk later. Serum-free medium was administered to age-matched mice as a control. Echocardiography and right ventricular systolic pressure (RVSP) measurements via right jugular vein catheterization were conducted 5 and 6 days after the second infection, respectively. Peripheral capillary oxygen saturation monitoring did not indicate hypoxia at 2-4 days post-RSV infection, before reinfection, and at 2-7 days after reinfection. RSV-infected mice had significantly higher RVSP than control mice. Pulsed-wave Doppler recording of the pulmonary blood flow by echocardiogram demonstrated a significantly shortened pulmonary artery acceleration time and decreased pulmonary artery acceleration time-to-ejection time ratio in RSV-infected mice. Morphometry showed that RSV-infected mice exhibited a significantly higher pulmonary artery medial wall thickness and had an increased number of muscularized pulmonary arteries compared with control mice. These findings, confirmed by RVSP measurements, demonstrate the development of PH in the lungs of mice infected with RSV as neonates. This animal model can be used to study the pathogenesis of PH secondary to RSV bronchiolitis and to assess the effect of treatment interventions. NEW & NOTEWORTHY This is the first mouse model of respiratory syncytial virus-induced pulmonary hypertension, to our knowledge. This model will allow us to decipher molecular mechanisms responsible for the pathogenesis of pulmonary hypertension secondary to respiratory syncytial virus bronchiolitis with the use of knockout and/or transgenic animals and to monitor therapeutic effects with echocardiography.
肺高血压（PH）在患有中度至重度呼吸道合胞病毒（RSV）细支气管炎的婴儿中高达 75%，并与患有先天性心脏病的婴儿的发病率和死亡率显著相关。本研究的目的是建立一种模拟婴儿中发生的疾病病因的 RSV 细支气管炎继发 PH 的小鼠模型。在 5 天大时用 RSV 感染新生小鼠，然后在 4 周后再次感染。将无血清培养基给予年龄匹配的小鼠作为对照。在第二次感染后分别通过右颈静脉导管进行 5 和 6 天的超声心动图和右心室收缩压（RVSP）测量。外周毛细血管血氧饱和度监测在 RSV 感染后 2-4 天、再次感染前和再次感染后 2-7 天未显示缺氧。RSV 感染的小鼠的 RVSP 明显高于对照组。通过超声心动图的脉冲波多普勒记录肺血流，RSV 感染的小鼠的肺动脉加速时间明显缩短，肺动脉加速时间与射血时间的比值降低。形态计量学显示，与对照组相比，RSV 感染的小鼠的肺动脉中层壁厚度明显增加，并且肌型肺动脉的数量增加。这些发现通过 RVSP 测量得到了证实，表明新生期感染 RSV 的小鼠肺部发生 PH。该动物模型可用于研究 RSV 细支气管炎继发 PH 的发病机制，并评估治疗干预的效果。
据我们所知，这是第一个呼吸道合胞病毒诱导的肺动脉高压的小鼠模型。该模型将使我们能够使用敲除和/或转基因动物来阐明导致呼吸道合胞病毒细支气管炎继发肺动脉高压的发病机制的分子机制，并通过超声心动图监测治疗效果。
