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

描述（由申请人提供）：补充氧广泛用于婴儿肺功能不全的治疗。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。本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。具体目的是：(1)验证野生型（WT） （C57BL/6J）小鼠产前或产后暴露于细胞色素P4501A1 （CYP1A1）诱诱剂β -萘黄酮（BNF）将分别导致新生儿高氧暴露引起的急性肺和肝损伤和肺异常成熟的衰减或增强的假设。野生型（WT） （C57BL/6J）小鼠在产前或产后接受玉米油（对照）或BNF处理，新生儿会早产。假设缺乏CYP1A1或肝脏特异性CYP1A2基因的新生小鼠更容易发生急性和长期氧致肺损伤。将新生野生型（C57BL/6J）、Cyp1a1（-/-）、Cyp1a2（-/-）或Cyp1a1/1a2双敲除小鼠暴露于室内空气或高氧环境中7天，在选定的时间点研究CYP1A的表达和肺、肝损伤参数。(3)探讨高氧诱导新生小鼠体内及培养细胞CYP1A1表达的分子机制。该目的有两个子目的：(i)验证高氧通过涉及相应启动子转录激活的机制诱导新生儿CYP1A1/1A2基因表达的假设。（ii）确定人CYP1A1基因对胎儿肺细胞的诱导作用机制。我们将验证高氧诱导人或小鼠胎儿肺细胞中CYP1A1表达的假设，通过AHR与特异性高氧再抑制hCYP1A1以肺特异性的方式相互作用，将比同样暴露的WT小鼠更不容易受到高氧肺损伤。建议的研究应该为制定新的合理策略来预防和治疗早产儿和足月婴儿的BPD和其他疾病提供概念基础。公共卫生相关性：补充氧被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部（如BPD）和其他与高氧相关疾病的新方法。

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.