Pulmonary implications of perinatal acetaminophen exposure
围产期对乙酰氨基酚暴露对肺部的影响
基本信息
- 批准号:10386049
- 负责人:
- 金额:$ 40.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcetaminophenAcuteAddressAdultAdverse effectsAffectAlveolarAnalgesicsAttenuatedBiologyBronchopulmonary DysplasiaCYP2E1 geneCell DeathCellsChildhoodClinicalClinical DataDataDevelopmentEnzymesExposure toFetal LungFunding OpportunitiesGrowthHepaticHepatocyteHepatotoxicityHuman DevelopmentHyperoxiaIminesImmune signalingImmunologyInjuryKnowledgeLifeLinkLiverLungMediatingMetabolic stressMetabolismMitochondriaMitochondrial DNAMusMyofibroblastNeonatalNeonatal Intensive Care UnitsNewborn InfantOutcomeOxidative StressPatent Ductus ArteriosusPathway interactionsPerceptionPerinatalPerinatal ExposurePharmacologyPhysiologyPlacentaPopulationPositioning AttributePredispositionPregnancyQuinonesReportingRiskSafetySignal TransductionSliceStressStructural defectStructureTestingToxic effectToxinXenobioticscell typeclinically relevantdrug actionexperimental studyfetalgain of functiongenetic approachhepatocellular injuryimmune activationimprovedin uteroin vivolung developmentlung injurymaternal safetymedication safetyneonatal exposureneonatal lung injurynovelopioid exposurepostnatalpre-clinicalpreclinical developmentpreclinical studypregnantprenatalpreterm newbornreceptorrespiratoryresponsestressortherapeutic target
项目摘要
PROJECT SUMMARY
Acetaminophen (APAP)is one of the most commonly used analgesics in the world, andoverwhelmingly
perceived to be safe. This perception has contributed to ubiquitous exposures during gestation and among
newborns in the neonatal intensive care unit. These exposures occur during critical windows of human
development where pre-clinical and clinical data demonstrating safety are lacking. Alarmingly, clinical data
support the hypothesis that the developing lung may be adversely affected by perinatal APAP exposures. The
toxicity of APAP is dependent on its conversion by the xenobiotic-metabolizing enzyme CYP2E1 the
mitochondrial toxin N-acetyl-para-benzo-quinone imine (NAPQI). Our preliminary data demonstrate that
pulmonary CYP2E1 expression peaks during the saccular stage of development and is limited to the
myofibroblast. Additionally, we show that postnatal APAP exposures induce Cyp2e1 expression in the late
saccular/early alveolar stage lung. Consistent with CYP2E1 expression, we show that the developing lung is
susceptible to APAP-induced injury. These preliminary data have led us to develop the following hypothesis:
The saccular/early alveolar stage lung is susceptible to APAP-induced injury due to developmentally-
regulated pulmonary CYP2E1 expression. We propose three specific aims to test this hypothesis. In Aim 1,
we will test the hypothesis that in utero APAP exposures during the saccular stage of lung development injure
pulmonary myofibroblasts and disrupt alveolarization. In Aim 2, we will test the hypothesis that postnatal APAP
exposures during the late saccular/early alveolar stage induce lung CYP2E1 expression causing oxidative
stress and increase sensitivity to injury. In Aim 3, we will test the hypothesis that inhibiting TLR9/NFκB innate
immune signaling will attenuate APAP-induced newborn lung injury. Our collaborative team bridging
developmental pulmonary biology, physiology, immunology and mitochondrial/oxidative stress biology is well
positioned to fill critical gaps in our understanding of the developmentally-regulated, cell-type specific CYP2E1
expression and APAP-induced lung injury. These studies will help determine the safety profile of APAP to
inform both maternal use and newborn exposures while identifying therapeutic targets to limit adverse effects.
into
项目摘要
对乙酰氨基酚(Acetaminophen,APAP)是世界上最常用的镇痛药之一,
被认为是安全的这种看法导致了怀孕期间和怀孕期间普遍存在的暴露,
新生儿重症监护室的新生儿。这些暴露发生在人类的关键窗口期间,
缺乏证明安全性的临床前和临床数据的开发。令人担忧的是,临床数据
支持这一假设,即发育中的肺可能受到围产期APAP暴露的不利影响。的
APAP的毒性取决于其通过异生物质代谢酶CYP 2 E1的转化,
线粒体毒素N-乙酰基-对苯醌亚胺(NAPQI)。我们的初步数据表明,
肺CYP 2 E1表达在发育的囊状期达到峰值,
肌成纤维细胞此外,我们发现,出生后APAP暴露诱导Cyp 2 e1表达的晚期,
囊状/早期肺泡期肺。与CYP 2 E1的表达一致,我们发现发育中的肺
易受APAP诱导的损伤。这些初步数据使我们提出了以下假设:
囊状/早期肺泡期肺易受APAP诱导的损伤,这是由于发育-
调节肺CYP 2 E1表达。我们提出了三个具体目标来检验这一假设。在目标1中,
我们将检验这一假设,即在肺发育的囊状阶段,
肺肌成纤维细胞和破坏肺泡化。在目标2中,我们将检验出生后APAP
在晚期囊状/早期肺泡阶段的暴露诱导肺CYP 2 E1表达,
增加对伤害敏感性。在目的3中,我们将检验抑制TLR 9/NFκB先天性
免疫信号传导将减弱APAP诱导的新生儿肺损伤。我们的协作团队
发育肺生物学、生理学、免疫学和线粒体/氧化应激生物学
定位于填补我们对发育调节的细胞类型特异性CYP 2 E1理解的关键空白
表达和APAP诱导的肺损伤。这些研究将有助于确定APAP的安全性,
告知产妇使用和新生儿接触,同时确定治疗目标,以限制不良影响。
成
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Clyde Jason Wright其他文献
Clyde Jason Wright的其他文献
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{{ truncateString('Clyde Jason Wright', 18)}}的其他基金
Pulmonary implications of perinatal acetaminophen exposure
围产期对乙酰氨基酚暴露对肺部的影响
- 批准号:
10593099 - 财政年份:2022
- 资助金额:
$ 40.86万 - 项目类别:
Pulmonary implications of perinatal acetaminophen exposure
围产期对乙酰氨基酚暴露对肺部的影响
- 批准号:
10755924 - 财政年份:2022
- 资助金额:
$ 40.86万 - 项目类别:
Role of hepatic IkBb-mediated sustained NFkB activation in neonatal lung injury and abnormal development
肝 IkBb 介导的持续 NFkB 激活在新生儿肺损伤和异常发育中的作用
- 批准号:
9258241 - 财政年份:2017
- 资助金额:
$ 40.86万 - 项目类别:
The unique role of IkBa in modulating NF-kB activity in the newborn lung.
IkBa 在调节新生肺中 NF-kB 活性方面的独特作用。
- 批准号:
8365422 - 财政年份:2010
- 资助金额:
$ 40.86万 - 项目类别:
The unique role of IkBa in modulating NF-kB activity in the newborn lung.
IkBa 在调节新生肺中 NF-kB 活性方面的独特作用。
- 批准号:
8242722 - 财政年份:2010
- 资助金额:
$ 40.86万 - 项目类别:
The unique role of IkBa in modulating NF-kB activity in the newborn lung.
IkBa 在调节新生肺中 NF-kB 活性方面的独特作用。
- 批准号:
8652491 - 财政年份:2010
- 资助金额:
$ 40.86万 - 项目类别:
The unique role of IkBa in modulating NF-kB activity in the newborn lung.
IkBa 在调节新生肺中 NF-kB 活性方面的独特作用。
- 批准号:
7772817 - 财政年份:2010
- 资助金额:
$ 40.86万 - 项目类别:
The unique role of IkBa in modulating NF-kB activity in the newborn lung.
IkBa 在调节新生肺中 NF-kB 活性方面的独特作用。
- 批准号:
8039962 - 财政年份:2010
- 资助金额:
$ 40.86万 - 项目类别:
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