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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：
10755924
负责人：
Clyde Jason Wright
金额：
$ 7.7万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
https://reporter.nih.gov/project-details/10755924
关键词：
Acetaminophen Acute Adult Adverse effects Affect Alveolar Analgesics Attenuated Award Biology Bronchopulmonary Dysplasia CYP2E1 gene Cell Death Cells Childhood Clinical Clinical Data Data Development Enzymes Exposure to Fetal Lung Funding Funding Opportunities Growth Hepatic Hepatocyte Hepatotoxicity Human Development Hyperoxia Imines Immune signaling Immunology Injury Knowledge Life Link Liver Lung Mediating Metabolic stress Metabolism Mitochondria Mitochondrial DNA Mus Myofibroblast Neonatal Neonatal Intensive Care Units Newborn Infant Outcome Oxidative Stress Parents Patent Ductus Arteriosus Pathway interactions Perception Perinatal Perinatal Exposure Physiology Placenta Population Positioning Attribute Predisposition Pregnancy Reporting Risk Safety Signal Transduction Slice Stress Structural defect Structure Testing Toxic effect Toxin Xenobiotics cell type clinically relevant drug action experimental study fetal gain of function genetic approach hepatocellular injury immune activation improved in utero in vivo loss of function lung development lung injury maternal safety medication safety neonatal exposure neonatal lung injury novel opioid exposure para-benzoquinone parent grant pharmacologic postnatal pre-clinical preclinical development preclinical study pregnant prenatal preterm newborn receptor respiratory morbidity response stressor therapeutic target

项目摘要

PROJECT SUMMARY OF THE FUNDED PARENT AWARD Acetaminophen (APAP)is one of the most commonly used analgesics in the world, and overwhelmingly 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

受资助家长奖项目摘要对乙酰氨基酚 (APAP) 是世界上最常用的镇痛药之一，绝大多数被认为是安全的。这种观念导致了妊娠期间和儿童中普遍存在的暴露新生儿重症监护病房的新生儿。这些暴露发生在人类生命的关键时期缺乏证明安全性的临床前和临床数据的开发。令人震惊的是，临床数据支持以下假设：发育中的肺部可能会受到围产期 APAP 暴露的不利影响。这 APAP 的毒性取决于其被异生素代谢酶 CYP2E1 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 CYP2E1 表达在囊状发育阶段达到峰值，并且仅限于肌成纤维细胞。此外，我们发现出生后 APAP 暴露会诱导晚期 Cyp2e1 表达。囊状/早期肺泡期肺。与 CYP2E1 表达一致，我们表明发育中的肺是易受 APAP 引起的损伤。这些初步数据使我们得出以下假设：囊状/早期肺泡期肺容易受到 APAP 诱导的损伤，因为发育- 调节肺 CYP2E1 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，我们将检验以下假设：肺发育囊泡阶段的子宫内 APAP 暴露会造成损伤肺肌成纤维细胞并破坏肺泡化。在目标 2 中，我们将检验出生后 APAP 的假设囊状晚期/肺泡早期暴露会诱导肺 CYP2E1 表达，从而引起氧化应激并增加对伤害的敏感性。在目标 3 中，我们将检验抑制 TLR9/NFκB 先天免疫的假设信号传导将减轻 APAP 引起的新生儿肺损伤。我们的协作团队在发展中架起桥梁肺生物学、生理学、免疫学和线粒体/氧化应激生物学能够很好地填补这一空白。我们对发育调节、细胞类型特异性 CYP2E1 表达的理解存在关键差距 APAP 引起的肺损伤。这些研究将有助于确定 APAP 的安全性，以告知产妇使用和新生儿暴露，同时确定治疗目标以限制不良反应。进入