Molecular Mechanisms of Neonatal Pulmonary Hemorrhage

摘要 肺血管系统的独特之处在于它的血液动力学发生了显著的变化。 在出生后立即施加力量。第一次呼吸时氧分压升高会导致氧分压降低 肺血管阻力，伴随着动脉导管的关闭和 卵圆孔，导致通过肺血管的血流量显著增加。 虽然大多数婴儿可以通过血管对血流动力的这种变化做出反应 稳定和成熟时，出现并发症的人可能会死于呼吸衰竭。 和死亡。新生儿肺出血(NPH)是一种并发症，发生在大约1/4的病例中。 1000个新生儿。我们假设，肺动脉的正常成熟失败，包括 阻断血流诱导的ERK5激活，是NPH的一个重要机制。目前，NPH缺乏任何 明确的病因和常规治疗仍然是主要的支持性治疗。我们建议测试一下 假设在肺中过量产生生长因子血管生成素2(ANGPT2)，这是 ERK5信号转导中断的结果，是婴幼儿白血病治疗的一个关键的靶向机制。 NPH。利用小鼠遗传和药理学模型以及体外研究相结合的方法，我们 建议测试ERK5-ANGPT2通路在促进血管内皮细胞稳定中的相关作用 新生儿关键时期的肺血管系统。我们的最终目标将是开发新的 NPH的治疗策略，可能适用于其他肺血管情况 不稳定。

Abstract The pulmonary vasculature is unique in that it is subjected to a remarkable change in hemodynamic forces immediately after birth. Increase in oxygen tension with the first breath results in decreased pulmonary vascular resistance, which in conjunction with closure of the ductus arteriosus and foramen ovale, leads to marked increase in the blood flow through the pulmonary blood vessels. While the majority of infants can respond to such a change in hemodynamic forces via vascular stabilization and maturation, those in whom complications occur can succumb to respiratory failure and death. Neonatal pulmonary hemorrhage (NPH) is such a complication occurring in about 1 in 1000 births. We hypothesize that failure of proper maturation of the pulmonary arteries, involving disruption of flow induced ERK5 activation, is a key mechanism of NPH. Currently NPH lacks any well-defined etiology and conventional therapy remains mainly supportive. We propose to test the hypothesis that excess production of the growth factor Angiopoietin 2 (ANGPT2) in the lung, which results from disrupted ERK5 signaling, is a key therapeutically targetable mechanism in infants with NPH. Using a combination of mouse genetic and pharmacologic models and in vitro studies, we propose to test the relevant role of the ERK5-ANGPT2 pathway in promoting stabilization of the pulmonary vasculature in the pivotal newborn period. Our ultimate goal will be to develop new therapeutic strategies for NPH, which may be applicable to other contexts of pulmonary vascular instability.