Hydrogen Sulfide in Neonatal Airway Disease
新生儿气道疾病中的硫化氢
基本信息
- 批准号:10603293
- 负责人:
- 金额:$ 61.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:3 year oldAdultAffectAgeAgonistAirway DiseaseAirway FibrosisAlveolarAsthmaBiochemicalBronchodilationBronchopulmonary DysplasiaCell RespirationCell modelChildChildhoodCyclic AMPDataDevelopmentEnzymesEpitheliumEquilibriumExposure toExtracellular MatrixFetal LungFetal ReductionFibrosisFunctional disorderFutureGenerationsGlutathioneGoalsGrowthHIF1A geneHistologyHumanHydrogen SulfideHyperoxiaHypoxiaImageImaging TechniquesImpairmentIn VitroInflammatoryInvestigationLifeLungMethionineMitochondriaModelingMolecularMusMuscle MitochondriaNeonatalNeonatal Intensive Care UnitsNewborn InfantObstructionOxidative StressOxygenPathway interactionsPerinatalPregnancyPremature InfantProliferatingRecoveryRegulationRiskRisk ReductionRoleS-AdenosylhomocysteineS-AdenosylmethionineSignal PathwaySignal TransductionSliceStructureSystemTechniquesTherapeuticTractionVulnerable PopulationsWorkairway hyperresponsivenessairway remodelingbody systemcell typeclinically relevantclinically significantfetalhigh riskimprovedin vivolaser capture microdissectionmitochondrial dysfunctionmouse modelneonatal micenormoxianovelnovel therapeuticspharmacologicprematurepreterm newbornpuprespiratory smooth muscleresponsetherapeutic developmenttherapeutic target
项目摘要
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(<;60%)O2(高氧)可促进支气管气道高反应性(AHR)
通过对呼吸道平滑肌(ASM)的影响,这是一种也导致支气管扩张受损的细胞类型,以及
重塑(增殖,细胞外基质改变)。从而了解了O2通过
对脆弱人群的治疗策略来说,影响支气管呼吸道是至关重要的。我们提出了一个
硫化氢(H2S)在发育可用于早产儿的呼吸道中的保护作用,因此
为我们的建议提供了临床意义。我们假设保护性内源性硫化氢系统是
受到O2的有害影响,但外源H2S供体可以用来抵消
O2对收缩和重塑的影响。对内源硫化氢在发育过程中的调控知之甚少
以及适度氧气降低硫化氢的机制。相反,通过这些机制
硫化氢对发展中的呼吸道以缓解氧气影响的影响尚不清楚。我们提出了三个利用人类胎儿的目标
用肺和活体新生小鼠模型来探索这些概念。目标1:在发展人类ASM的过程中,
确定氧气对内源性硫化氢的影响;目标2:在人类ASM的发育中,通过以下方式确定机制
哪种硫化氢减轻O2增强的气道收缩和重塑;目标3:在新生小鼠模型中
高氧,确定硫化氢对气道收缩和重塑的影响。在目标1中,我们将使用18-22周
妊娠期人胎儿ASM(FASM)以研究O2降低H_2S的机制,重点是ROS,
线粒体,以及蛋氨酸-硫磺平衡的变化,这些变化可以推动硫化氢的变化
合成酶CBS。目标2探索硫化氢的下游影响(通过供体NAHS和GYY4137,以及
内源性硫化氢的增强)在40%O2后的收缩和重塑的背景下。在这里,
主要集中在三个关键机制上:抑制HIF1α、激活NRF2和增强cAMP。在AIM
3、体外研究采用新生小鼠高氧模型进行整合,在该模型中,早期暴露于中等浓度的
氧气水平会导致持续的AHR和重塑。硫化氢供体缓解AHR和AHR的疗效
对改建进行了评估。临床意义在于确定H_2S在氧分压中的重要性
为未来新生儿哮喘的治疗靶向发展呼吸道。
项目成果
期刊论文数量(0)
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Christina Maria Pabelick其他文献
Christina Maria Pabelick的其他文献
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