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：
10593099
负责人：
Clyde Jason Wright
金额：
$ 39.5万
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/10593099
关键词：
Acetaminophen Acute Adult Adverse effects Affect Alveolar Analgesics Attenuated Biology Bronchopulmonary Dysplasia CYP2E1 gene Cell Death Cells Childhood Clinical Clinical Data Data Development Enzymes Exposure to Fetal Lung 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 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 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 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（APAP）是世界上最常用的镇痛药之一，并且是助图被认为是安全的。这种看法导致妊娠期间无处不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的关键窗户中临床前和临床数据表明缺乏安全性的开发。令人震惊的是，临床数据支持以下假设：发育中的肺可能会受到围产期APAP暴露的不利影响。这 APAP的毒性取决于其转化率通过异种生物生物代谢CYP2E1 线粒体毒素n-乙酰基 - 帕拉 - 苯甲酮亚胺（NAPQI）。我们的初步数据表明肺CYP2E1表达在发育阶段的峰值，仅限于肌纤维细胞。此外，我们表明，产后APAP暴露会在晚期诱导CYP2E1表达肺泡/早期肺泡阶段肺。与CYP2E1表达一致，我们表明发育中的肺是容易受到APAP诱导的损伤。这些初步数据使我们提出了以下假设：肺泡/早期肺泡阶段肺易受APAP诱导的损伤，原因是调控肺CYP2E1表达。我们提出了三个特定的目的来检验这一假设。在AIM 1中，我们将检验以下假设，即在肺发育损伤的寒冷阶段，在子宫APAP暴露肺部肌纤维细胞并破坏肺泡化。在AIM 2中，我们将检验出产后APAP的假设晚期/早期肺泡阶段的暴露会影响肺CYP2E1表达，导致氧化压力并增加对伤害的敏感性。在AIM 3中，我们将测试抑制TLR9/NFκB先天的假设免疫信号传导会减弱APAP诱导的新生儿肺损伤。我们的协作团队桥接发育性肺生物学，生理，免疫学和线粒体/氧化应激生物学很好在我们对开发的细胞类型特定CYP2E1的理解中填补关键空白的位置表达和APAP诱导的肺损伤。这些研究将有助于确定APAP的安全性在确定治疗靶标以限制广告效果的同时，告知孕产妇使用和新生儿暴露。进入