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Role of hepatic and pulmonary P4501A enzymes in neonatal hyperoxic tissue injury

肝肺 P4501A 酶在新生儿高氧组织损伤中的作用

基本信息

批准号：
8304343
负责人：
XANTHI Ioanna COUROUCLI
金额：
$ 37.99万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8304343
关键词：
Acute Acute Lung Injury Air Animals Biological Assay Bronchopulmonary Dysplasia CYP1A2 gene Cell Communication Cell Culture Techniques Cells Chemosensitization Chronic lung disease Clara cell Corn Oil Cultured Cells Cytochrome P450 Cytochromes Development Disease Electrophoretic Mobility Shift Assay Embryo Enzymes F2-Isoprostanes Fetal Lung Flavonoids Foundations Gene Expression Genes Genetic Transcription Goals Health Hepatic Histology Human Hyperoxia Image Immunohistochemistry In Situ Hybridization Infant Inflammation Inflammatory Injury Irrigation Knock-out Knockout Mice Lipid Peroxidation Liver Luciferases Lung Lung diseases Mediating Messenger RNA Modeling Molecular Mothers Mus Neonatal Newborn Animals Newborn Infant Nuclear Organ Organ failure Oxygen Oxygen Therapy Care Play Premature Infant Prevention Prevention strategy Preventive Production Promoter Regions Proteins Pulmonary Edema Pulmonary Valve Insufficiency Reactive Oxygen Species Regulation Reporter Genes Research Response Elements Retinopathy of Prematurity Reverse Transcriptase Polymerase Chain Reaction Role Running Site-Directed Mutagenesis Southern Blotting Structure of parenchyma of lung Testing Therapeutic Intervention Time Tissues Transcriptional Activation Transgenes Transgenic Mice Transgenic Organisms Western Blotting Wild Type Mouse attenuation chromatin immunoprecipitation cytokine in vivo lung injury lung maturation morphometry neutrophil novel novel strategies postnatal pregnant prenatal prevent promoter protein expression receptor research study

项目摘要

DESCRIPTION (provided by applicant): Supplemental oxygen is used extensively in the treatment of pulmonary insufficiency in infants. In premature infants, hyperoxic therapies contribute to the development of bronchopulmonary dysplasia (BPD) and other multi-organ failures. The central hypothesis of the proposed study is that hepatic and pulmonary cytochrome P450 (CYP)1A enzymes play a protective role against acute and long-term injury to lung and other organs by oxygen. The specific aims are: (1) To test the hypothesis that prenatal or postnatal exposure of wild type (WT) (C57BL/6J) mice to the cytochrome P4501A1 (CYP1A1) inducer beta-naphthoflavone (BNF) will result in attenuation or potentiation, respectively, of acute lung and liver injury and abnormal lung maturation resulting from neonatal hyperoxic exposures. Newborn wild type (WT) (C57BL/6J) mice are subjected to prenatal or postnatal treatment with corn oil (vehicle control) or BNF, and newborns will be delivered prematurethe hypothesis that newborn mice lacking the genes for CYP1A1 or the liver- specific CYP1A2 will be more susceptible to acute and long-term lung injury induced by oxygen. Newborn wild type (C57BL/6J), Cyp1a1 (-/-), Cyp1a2 (-/-), or Cyp1a1/1a2 double knockout mice will be exposed to room air or hyperoxia for 7 days, and CYP1A expression and parameters of lung and liver injury will be studied at selected time points. (3) To determine the molecular mechanism of CYP1A1 induction by hyperoxia in the newborn mice in vivo and in cultured cells. This aim has two sub-aims: (i) To test the hypothesis that hyperoxia induces CYP1A1/1A2 gene expression in the newborn through mechanisms involving transcriptional activation of the corresponding promoters. (ii) To determine the mechanisms of induction of human CYP1A1 gene on fetal lung cells. We will test the hypothesis that hyperoxia induces CYP1A1 expression in human or mouse fetal lung cells by interaction of the AHR with specific hyperoxic respopressing the hCYP1A1 in a lung-spcific manner will be less susceptible to hyperoxic lung injury than similarly exposed WT mice. The proposed studies should provide conceptual foundation(s) for the development of novel rational strategies for the prevention and treatment of BPD and other diseases in preterm and term infants. PUBLIC HEALTH RELEVANCE: Supplemental oxygen is used extensively in the treatment of pulmonary insufficiency in infants. In premature infants, hyperoxic therapies contribute to the development of bronchopulmonary dysplasia (BPD) and other multi-organ failures. Using knockout and transgenic mice, and cell culture models, this project is aimed at developing novel approaches for the prevention and treatment of lung (e.g., BPD) and other diseases associated with hyperoxia.

描述（由申请人提供）：补充氧气广泛用于治疗婴儿肺功能不全。在早产儿中，高氧治疗有助于支气管肺发育不良（BPD）和其他多器官衰竭的发展。这项研究的中心假设是，肝和肺细胞色素P450（CYP）1A酶对氧对肺和其他器官的急性和长期损伤起保护作用。具体目标是：（1）检验野生型（WT）（C57 BL/6 J）小鼠出生前或出生后暴露于细胞色素P4501 A1（CYP 1A 1）诱导剂β-萘烷酮（BNF）将分别导致新生儿高氧暴露引起的急性肺和肝损伤以及异常肺成熟的减弱或增强的假设。新生野生型（WT）（C57 BL/6 J）小鼠在出生前或出生后接受玉米油（溶剂对照）或BNF治疗，新生小鼠将早产，这是因为缺乏CYP 1A 1或肝脏特异性CYP 1A 2基因的新生小鼠更容易受到氧诱导的急性和长期肺损伤的假设。将新生野生型（C57 BL/6 J）、Cyp 1a 1（-/-）、Cyp 1a 2（-/-）或Cyp 1a 1/1a 2双敲除小鼠暴露于室内空气或高氧7天，并在选定的时间点研究CYP 1A表达和肺和肝损伤参数。(3)探讨高氧对新生小鼠体内和培养细胞CYP 1A 1的诱导作用及其分子机制。这一目标有两个次级目标：（i）检验高氧通过涉及相应启动子转录激活的机制诱导新生儿CYP 1A 1/1A 2基因表达的假设。(ii)目的探讨人CYP 1A 1基因对胎肺细胞的诱导作用机制。我们将检验以下假设：高氧通过AHR与特异性高氧相互作用诱导人或小鼠胎肺细胞中CYP 1A 1的表达，以肺特异性方式重新表达hCYP 1A 1的小鼠对高氧肺损伤的敏感性低于类似暴露的WT小鼠。拟议的研究应为制定预防和治疗早产儿和足月儿BPD和其他疾病的新的合理策略提供概念基础。公共卫生相关性：补充氧气广泛用于治疗婴儿肺功能不全。在早产儿中，高氧治疗有助于支气管肺发育不良（BPD）和其他多器官衰竭的发展。利用基因敲除和转基因小鼠以及细胞培养模型，该项目旨在开发预防和治疗肺（例如，BPD）和其他与高氧相关的疾病。