A Safer Glucocorticoid to Treat Neonatal Lung Injury with Limited Adverse Neurologic Effects

支气管肺发育不良(Bpd)仍然是早产儿的重要并发症。 在出生28周的≤婴儿中，有近70%受到影响。当前的药物治疗策略 缓解BPD的发展和进展，包括管理长效 合成糖皮质激素(SGC)，如地塞米松(Dex)。几个随机化 临床试验证实sGC疗法针对肺部发育的早产儿 伤害大大降低了BPD的风险，但阻碍了与不利因素相关的重大风险 躯体生长和大脑结构和功能的长期变化。因此， 仍然迫切需要GC药物疗法来治疗新生儿BPD，这将 提供有益的抗炎和肺成熟作用，但不良反应有限 对大脑的影响。环索奈德(ciclesonide，CIC)是目前开发的新一代吸入型sgc。 批准用于治疗哮喘和过敏性鼻炎，不会引起全身性 在其他SGCs中经常观察到不良反应。临床试验也显示没有 CIC对2岁儿童服用安慰剂以外的不良反应。我们假设中投公司将 减轻高氧诱导的新生儿急性肺损伤，但不触发 新生儿脑内脱髓鞘、星形胶质细胞增多症、小胶质细胞活化或神经元损伤 由系统管理的sGC引起，如Dex。三个具体目标是 建议用一个多学科团队来验证这一假设，该团队有能力 同时研究其体外机制和高度相关的啮齿动物模型 新生儿肺损伤。目标1将确定CIC通过哪些机制防止 实验性bpd高氧性急性肺损伤与肺泡重塑。目标2 将确定新生儿单个细胞类型对CIC的转录反应 利用scRNA-Seq.目标3将比较急性和长期 新生儿地塞米松与CIC暴露对大脑结构和行为的影响。 这项研究有可能确定CIC是治疗BPD合并脑损伤的有效的sGC疗法。 节制效应，解决目前预防和/或治疗BPD的治疗方法的匮乏 早产儿。

Bronchopulmonary dysplasia (BPD) remains a significant complication of prematurity affecting nearly 70% in infants born ≤28 weeks. Current pharmacologic strategies to mitigate the development and progression of BPD include administration of long-acting synthetic glucocorticoids (sGCs) such as dexamethasone (Dex). Several randomized clinical trials establish that sGC therapy targeted to preterm infants with evolving lung injury decreases BPD risk substantially, but encumber significant risks related to adverse somatic growth and long-lasting alterations in brain structure and function. Therefore, there remains an urgent need for GC pharmacotherapy for BPD in neonates that will provide beneficial anti-inflammatory and lung maturation effects, but limited adverse effects on the brain. Ciclesonide (CIC) is a new generation inhaled sGC currently approved for the treatment of asthma and allergic rhinitis that does not cause systemic adverse effects often observed with other sGCs. Clinical trials also demonstrate no adverse effects of CIC beyond placebo in 2-year olds. We hypothesize that CIC will attenuate hyperoxia-mediated acute lung injury in neonates but NOT trigger the demyelination, astrogliosis, microglia activation or neuronal damage in neonatal brain caused by systemically administered sGCs such as Dex. Three Specific Aims are proposed to test this hypothesis with a multi-disciplinary team possessing the ability to simultaneously investigate in vitro mechanisms and highly relevant rodent models of neonatal lung injury. Aim 1 will determine the mechanisms by which CIC prevents hyperoxia-induced acute lung injury and alveolar remodeling in experimental BPD. Aim 2 will identify the transcriptomic responses to CIC within individual cell types of neonatal mouse lungs using scRNA-Seq. Aim 3 will compare the acute and long-term consequences of neonatal Dex versus CIC exposure on brain architecture and behavior. This study has potential to identify CIC as an effective sGC therapy for BPD with brain- sparing effects, addressing the current dearth of therapies to prevent and/or treat BPD in preterm infants.