Mechanisms of Hydrocortisone Regulation of the Perinatal Pulmonary Vasculature

支气管肺发育不良(BPD)每年影响10,000名早产儿，估计成本为 24亿美元。多达三分之一患有BPD的婴儿会继续发展为肺动脉高压(PH)，导致病情恶化。 长期结果和增加的死亡率。到目前为止，还没有确定有效的治疗BPD的方法- 相关PH值。然而，来自动物模型的数据表明，磷酸二酯酶-5(PDE5)和细胞外 超氧化物歧化酶(EcSOD)有望成为治疗PH的靶点。PDE5有助于 通过分解循环鸟苷一磷酸(CGMP)来收缩血管，cGMP是一种关键的肺血管扩张剂。 我们之前已经证明，氧化应激是高氧肺小鼠模型中的一个关键介质 损伤，激活PDE5，导致肺血管重构。抗氧化剂EcSOD的高效表达 已经被证明可以保护新生小鼠的肺免受高氧的伤害。 我们在高氧性肺损伤小鼠模型中发表的初步数据表明 氢化可的松，一种已知对早产儿安全的糖皮质激素，使高氧诱导的正常化 体外可激活PDE5，增加ECSOD蛋白，体内可减少右室肥厚。我们 相信氢化可的松对肺血管有直接作用，因此代表了一种新的 新生儿肺动脉高压的治疗。我们的中心假设是，HC逆转了高氧- 通过减弱异常的PDE5活性和诱导肺血管改变 通过上调EcSOD造成的氧化应激。我们将利用分离的小鼠肺动脉平滑肌 细胞，高氧性肺损伤的小鼠模型，和EcSOD基因敲除小鼠来表征直接的 氢化可的松对肺血管系统和血管信号通路的影响。这些发现将奠定 氢化可的松作为治疗肺动脉高压的新疗法的基础，并增加了新的 了解PDE5和EcSOD在BPD相关性PH的病理生理学和治疗中的作用。 候选人的长期职业目标是成为一名拥有专业知识的独立资助的研究人员 在糖皮质激素信号和肺血管病理生理学方面。颁奖期间的短期目标 阶段是阐明糖皮质激素影响新生儿的具体途径和机制 肺血管系统。应聘者的职业发展计划包括教学和技能获得 培训、职业发展活动和有指导的研究经验。这项创新工作将是 由肺血管生物学和一氧化氮信号通路专家凯瑟琳·法罗博士指导 在经验丰富的咨询团队的额外指导下，在肺血管系统方面进行了研究。这项工作是 在西北大学学术环境的称赞下，肺的力量 儿科正在进行的研究，以及新生儿科的承诺 以及儿科对初级临床医生科学家的支持和发展。

Bronchopulmonary dysplasia (BPD) affects 10,000 premature infants annually with an estimated cost of $2.4 billion. Up to a third of infants with BPD go on to develop pulmonary hypertension (PH), leading to worse long-term outcomes and increased mortality. Thus far, no effective therapies have been identified for BPD- associated PH. However, data from animal models suggest that phosphodiesterase-5 (PDE5) and extracellular superoxide dismutase (ecSOD) may hold promise as therapeutic targets in PH. PDE5 contributes to vasoconstriction by catabolizing cyclic guanosine monophosphate (cGMP), a critical pulmonary vasodilator. We have previously demonstrated that oxidative stress, a key mediator in the mouse model of hyperoxic lung injury, activates PDE5 and leads to pulmonary vascular remodeling. Overexpression of the antioxidant ecSOD has been shown to protect the lung against hyperoxia in the newborn mouse. Our published and preliminary data in the mouse model of hyperoxic lung injury demonstrates that hydrocortisone, a glucocorticoid with a known safety profile in premature infants, normalizes hyperoxia-induced PDE5 activation and increases ecSOD protein in vitro, and decreases right ventricular hypertrophy in vivo. We believe that hydrocortisone has a direct effect on the pulmonary vasculature and thus represents a novel treatment for neonatal pulmonary hypertension. Our central hypothesis is that HC reverses hyperoxia- induced changes in the pulmonary vasculature through attenuation of aberrant PDE5 activity and oxidative stress via upregulation of ecSOD. We will utilize isolated mouse pulmonary artery smooth muscle cells, the murine model of hyperoxia-induced lung injury, and ecSOD knockout mice to characterize the direct effects of hydrocortisone on pulmonary vasculature and on vascular signaling pathways. These findings will lay the foundation for the use of hydrocortisone as novel therapy in pulmonary hypertension, and add new knowledge about the role of PDE5 and ecSOD in pathophysiology and treatment of BPD-associated PH. The candidate’s long-term career goal is to become an independently funded researcher with expertise in glucocorticoid signaling and pulmonary vascular pathophysiology. The short-term goal during the award period is to elucidate the specific pathways and mechanisms by which glucocorticoids affect neonatal pulmonary vasculature. The candidate’s career development plan involves didactic and skill acquisition training, career development activities, and a mentored research experience. This innovative work will be mentored by Dr. Kathryn Farrow, an expert in pulmonary vascular biology and nitric oxide signaling pathways in the pulmonary vasculature, with additional guidance of a highly experienced advisory team. This work is complimented by the academic environment at Northwestern University, the strength of the pulmonary research being conducted in the Department of Pediatrics, and the commitment of the Division of Neonatology and the Department of Pediatrics to the support and development of junior clinician scientists.