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

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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.