Hydrogen Sulfide in Neonatal Airway Disease

新生儿气道疾病中的硫化氢

• 批准号: 10603293
• 负责人: Christina Maria Pabelick
• 金额: $ 61.12万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603293
• 关键词: 3 year old; Adult; Affect; Age; Agonist; Airway Disease; Airway Fibrosis; Alveolar; Asthma; Biochemical; Bronchodilation; Bronchopulmonary Dysplasia; Cell Respiration; Cell model; Child; Childhood; Cyclic AMP; Data; Development; Enzymes; Epithelium; Equilibrium; Exposure to; Extracellular Matrix; Fetal Lung; Fetal Reduction; Fibrosis; Functional disorder; Future; Generations; Glutathione; Goals; Growth; HIF1A gene; Histology; Human; Hydrogen Sulfide; Hyperoxia; Hypoxia; Image; Imaging Techniques; Impairment; In Vitro; Inflammatory; Investigation; Life; Lung; Methionine; Mitochondria; Modeling; Molecular; Mus; Muscle Mitochondria; Neonatal; Neonatal Intensive Care Units; Newborn Infant; Obstruction; Oxidative Stress; Oxygen; Pathway interactions; Perinatal; Pregnancy; Premature Infant; Proliferating; Recovery; Regulation; Risk; Risk Reduction; Role; S-Adenosylhomocysteine; S-Adenosylmethionine; Signal Pathway; Signal Transduction; Slice; Structure; System; Techniques; Therapeutic; Traction; Vulnerable Populations; Work; airway hyperresponsiveness; airway remodeling; body system; cell type; clinically relevant; clinically significant; fetal; high risk; improved; in vivo; laser capture microdissection; mitochondrial dysfunction; mouse model; neonatal mice; normoxia; novel; novel therapeutics; pharmacologic; premature; preterm newborn; pup; respiratory smooth muscle; response; therapeutic development; therapeutic target

ABSTRACT Moderate (<60%) O2 (hyperoxia) in premature infants promotes bronchial airway hyperresponsiveness (AHR) via effects on airway smooth muscle (ASM), a cell type that also contributes to impaired bronchodilation, and remodeling (proliferation, altered extracellular matrix (ECM)). Thus understanding mechanisms by which O2 affects bronchial airways is critical for therapeutic strategies in a vulnerable population. We propose a protective role for hydrogen sulfide (H2S) in developing airways that can be leveraged in prematurity, thus providing clinical significance to our proposal. We hypothesize that the protective endogenous H2S system is detrimentally influenced by O2, but that exogenous H2S donors can be used to counteract detrimental effects of O2 on contractility and remodeling. Little is known regarding regulation of endogenous H2S in developing bronchial airways, and mechanisms by which moderate O2 reduces H2S. Conversely, the mechanisms by which H2S impacts on developing airways to alleviate O2 effects are unknown. We propose 3 Aims using human fetal lung and in vivo neonatal mouse models of O2 to explore these concepts. Aim 1: In developing human ASM, determine influence of O2 on endogenous H2S; Aim 2: In developing human ASM, determine mechanisms by which H2S alleviates O2-enhanced airway contractility and remodeling; Aim 3: In a newborn mouse model of hyperoxia, determine effects of H2S on airway contractility and remodeling. In Aim 1, we will use 18-22 wk gestation human fetal ASM (fASM) to examine mechanisms by which O2 decreases H2S, focusing on ROS, mitochondria, and alterations in the methionine-transsulfuration balance that can drive changes in the H2S synthesis enzyme CBS. Aim 2 explores downstream effects of H2S (via donors NaHS and GYY4137, and enhancement of endogenous H2S) in the context of contractility and remodeling following 40% O2. Here, the focus is on three key mechanisms: suppression of HIF1α, activation of Nrf2, and enhancement of cAMP. In Aim 3, in vitro studies are integrated using a newborn mouse model of hyperoxia where early exposure to moderate oxygen levels results in sustained AHR and remodeling. The efficacy of H2S donors in alleviating AHR and remodeling is assessed. Clinical significance lies in establishing the importance of H2S in O2 effects on developing airway towards future therapeutic targeting for neonatal asthma.

摘要 早产儿中度（<60%）O2（高氧）促进支气管气道高反应性（AHR） 通过对气道平滑肌（ASM）的影响，ASM是一种也有助于支气管扩张受损的细胞类型， 重塑（增殖、改变的细胞外基质（ECM））。从而了解O2 影响支气管气道是治疗策略的关键在一个脆弱的人口。我们提出了一个 硫化氢（H2S）在早产儿气道发育中的保护作用， 为我们的建议提供临床意义。我们假设保护性内源性H2S系统是 O2的有害影响，但外源H2S供体可用于抵消 O2对收缩力和重塑的影响。关于内源性H2S在发育中的调节知之甚少， 支气管气道，以及适度O2减少H2S的机制。相反， H2S对气道发育的影响，以减轻O2的影响是未知的。我们提出了3个目的，利用人类胎儿 肺和体内新生小鼠模型的O2探索这些概念。目标1：在开发人类ASM时， 确定O2对内源性H2S的影响;目的2：在发展人类ASM时，通过以下方式确定机制： 其中H2S抑制了O2增强的气道收缩和重塑;目的3：在新生小鼠模型中， 高氧，确定H2S对气道收缩性和重塑的影响。在目标1中，我们将使用18-22周 妊娠人胎儿ASM（fASM），以检查O2降低H2S的机制，重点是ROS， 线粒体，以及甲硫氨酸转硫平衡的改变，可以驱动H2S的变化 合成酶CBS。目的2探索了H2S的下游效应（通过供体NaHS和GYY 4137，以及 内源性H2S的增强）在40%O2后的收缩性和重塑的背景下。这里 目前的研究主要集中在三个关键机制上：抑制HIF 1 α、激活Nrf 2和增强cAMP。在Aim中 3、体外研究采用新生小鼠高氧模型，其中早期暴露于中度 氧水平导致持续的AHR和重塑。H2S供体在缓解AHR和 重建评估。临床意义在于确定H2S在O2影响中的重要性， 开发气道，以实现新生儿哮喘的未来治疗目标。