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
• 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
• 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

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

项目总结 对乙酰氨基酚(APAP)是世界上最常用的止痛药之一，其镇痛效果令人惊叹 认为是安全的。这种看法导致了在怀孕期间和在 新生儿重症监护病房中的新生儿。这些暴露发生在人类的关键时间段 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 支持发育中的肺可能受到围产期APAP暴露的不利影响的假设。这个 APAP的毒性依赖于外源代谢酶CYP2E1对其的转化 线粒体毒素N-乙酰-对苯二酚亚胺(NAPQI)。我们的初步数据表明 肺组织中细胞色素P4502的表达在球囊发育阶段达到高峰，并仅限于 肌成纤维细胞。此外，我们还发现，出生后暴露于APAP可诱导晚期细胞色素P4502基因的表达。 囊状/早期肺泡期肺。与CYP2E1的表达一致，我们表明发育中的肺是 易受APAP诱导的损伤。这些初步数据使我们得出了以下假设： 囊状/早期肺泡期肺易受APAP诱导的损伤，这是由于发育性肺损伤 调节肺组织细胞色素P4502的表达。我们提出了三个具体目标来检验这一假设。在目标1中， 我们将检验这样一种假设，即在肺发育的球囊阶段，宫内暴露于APAP会造成损害 肺肌成纤维细胞和肺泡化紊乱。在目标2中，我们将检验出生后APAP的假设 球囊晚期/肺泡早期暴露可诱导肺组织细胞色素P4502的表达，引起氧化反应 应激并增加对伤害的敏感性。在目标3中，我们将检验先天抑制TLR9/NFκB的假设 免疫信号将减轻APAP所致的新生儿肺损伤。我们的协作团队架起桥梁 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CYP2E1理解中的关键空白 表达与APAP诱导的肺损伤。这些研究将有助于确定APAP的安全性 告知母亲使用和新生儿暴露，同时确定治疗目标，以限制不良反应。 vt.进入，进入