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

一种更安全的糖皮质激素治疗新生儿肺损伤且不良神经系统影响有限

• 批准号: 10312167
• 负责人: Donald B DeFranco
• 金额: $ 60.68万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10312167
• 关键词: 2 year old; 5 year old; Academy; Acute; Acute Lung Injury; Address; Adrenal Glands; Adult; Adverse effects; Affect; Agonist; Air; Allergic rhinitis; Alveolar; American; Animal Model; Anti-Inflammatory Agents; Architecture; Asthma; Attenuated; Behavior; Bone Growth; Brain; Bronchopulmonary Dysplasia; Cerebral Palsy; Child; Childhood; Clinical Practice Guideline; Clinical Trials; Complication; Demyelinations; Development; Dexamethasone; Dose; Fatty Acids; Fibrosis; Generations; Glucocorticoid Receptor; Glucocorticoids; Goals; Growth; Hyperoxia; In Vitro; Individual; Infant; Inflammation; Inhalation; Injury; Liquid Chromatography; Lung; Lung Inflammation; Mass Spectrum Analysis; Measures; Mediating; Microglia; Molecular; Neonatal; Neurologic; Neurologic Effect; Neurons; Oligonucleotides; Patients; Pediatrics; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Placebos; Premature Infant; Prodrugs; Randomized Clinical Trials; Recommendation; Resolution; Risk; Rodent Model; Structure; Testing; Therapeutic; Vulnerable Populations; astrogliosis; carboxylesterase; cell type; dosage; innovation; long bone; lung injury; lung maturation; multidisciplinary; myelination; neonatal brain; neonatal lung injury; neonatal mice; neonate; novel; novel therapeutics; premature; prevent; response; side effect; single-cell RNA sequencing; targeted treatment; transcriptomics

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.

支气管肺发育不良（BPD）仍然是早产儿的一个重要并发症 在≤28周出生的婴儿中影响近70%。目前的药理学策略， 缓解BPD的发展和进展，包括给予长效 合成糖皮质激素（sGC），如地塞米松（Dex）。几项随机 临床试验证实，sGC治疗针对肺发育不全的早产儿， 损伤大大降低了BPD风险，但阻碍了与不良反应相关的重大风险。 躯体生长和大脑结构和功能的长期改变。因此，我们认为， 对于新生儿BPD的GC药物治疗仍然存在迫切的需求， 提供有益的抗炎和肺成熟作用，但有限的副作用 对大脑的影响。环索奈德（CIC）是目前新一代吸入性sGC 批准用于治疗哮喘和过敏性鼻炎， 在其他sGC中经常观察到的不良反应。临床试验也表明， CIC对2岁奥尔兹的不良影响超过安慰剂。我们假设作战信息中心 减轻新生儿高氧介导的急性肺损伤，但不触发 新生儿脑中的脱髓鞘、星形胶质细胞增生、小胶质细胞活化或神经元损伤 由全身给予sGC（例如Dex）引起。三个具体目标是 建议用一个多学科的团队来测试这个假设， 同时研究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防止 实验性BPD中高氧诱导急性肺损伤和肺泡重塑目的2 将鉴定新生儿单个细胞类型中对CIC的转录组学反应， 使用scRNA-Seq.目标3将比较急性和长期 新生儿Dex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作为BPD的有效sGC疗法， 保留效应，解决目前缺乏预防和/或治疗BPD的治疗方法， 早产儿