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.

抽象的 早产儿中度（<60%）O2（高氧）会促进支气管气道高反应性 (AHR) 通过对气道平滑肌（ASM）的影响，这种细胞类型也会导致支气管扩张受损，以及 重塑（增殖、改变细胞外基质 (ECM)），从而了解 O2 的机制。 影响支气管气道对于弱势群体的治疗策略至关重要。 硫化氢（H2S）在气道发育中的保护作用可以在早产儿中利用，因此 我们勇敢地说，保护性内源性 H2S 系统具有临床意义。 受 O2 的不利影响，但外源 H2S 供体可用于抵消 O2 的不利影响 O2 对收缩性和重塑的影响对于发育过程中内源性 H2S 的调节知之甚少。 支气管气道，以及适度的 O2 减少 H2S 的机制。 H2S 对发育中的气道以减轻 O2 影响的影响尚不清楚，我们提出了使用人类胎儿的 3 个目标。 目的 1：开发人类 ASM， 确定 O2 对内源性 H2S 的影响；目标 2：在开发人类 ASM 时，通过以下方式确定机制： H2S 可减轻 O2 增强的气道收缩力和重塑；目标 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。 妊娠期人类胎儿 ASM (fASM)，用于检查 O2 减少 H2S 的机制，重点关注 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。目标 2 探索 H2S 的下游影响（通过供体 NaHS 和 GYY4137，以及 内源性 H2S 的增强）在 40% O2 后的收缩性和重塑中。 重点关注三个关键机制：抑制 HIF1α、激活 Nrf2 和增强 In Aim。 3、利用新生小鼠高氧模型进行体外研究，其中早期暴露于中度 氧气水平导致持续的 AHR 和重塑 H2S 供体在减轻 AHR 和重塑方面的功效。 评估重塑的临床意义在于确定 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。