Role of cytochrome P4501B1 in oxygen-mediated pulmonary injury

细胞色素 P4501B1 在氧介导的肺损伤中的作用

• 批准号: 8586889
• 负责人: BHAGAVATULA MOORTHY
• 金额: $ 41.59万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586889
• 关键词: Adult; Adult Respiratory Distress Syndrome; Aspirate substance; Biological Markers; Bronchopulmonary Dysplasia; CYP1B1 gene; Chronic lung disease; Clara cell; Cytochrome P450; DNA Adducts; DNA lesion; Development; Dinucleoside Phosphates; Disease; Endothelial Cells; Enzymes; F2-Isoprostanes; Genes; Genetic Polymorphism; Goals; Hepatic; Human; Hyperoxia; Indoles; Infant; Injury; Knockout Mice; Lead; Ligands; Lipid Peroxidation; Lung; Lung diseases; Mediating; Molecular; Mus; Oxygen; Play; Predisposition; Premature Infant; Prevention; Prevention strategy; Preventive; Pulmonary Valve Insufficiency; Pyruvic Acid; Reactive Oxygen Species; Research; Respiratory distress; Risk Factors; Role; Testing; Therapeutic; Time; Wild Type Mouse; adduct; cell type; environmental chemical; in vivo; inhibitor/antagonist; liquid chromatography mass spectrometry; lung injury; novel; novel strategies; oxidative DNA damage; protective effect; public health relevance; receptor

DESCRIPTION (provided by applicant): Hyperoxia is routinely used to treat respiratory distress and lung inadequacy in preterm and term infants. However, excess oxygen contributes to the development of chronic lung disease (CLD), which is also called bronchopulmonary dysplasia (BPD). The molecular mechanisms of hyperoxia-mediated pulmonary injury are not understood, but reactive oxygen species (ROS), which are also produced by environmental chemicals, are the most likely candidates. The central hypothesis of the proposed research is that pulmonary cytochrome P450 (CYP)1B1 plays a key role in hyperoxic lung injury by (i) acting as a pro-oxidant, leading to enhanced formation of lipid peroxidation products (e.g., F2-isoprostanes, isofurans) that in turn mediate lung injury; (ii) inactivating novel endogenous AHR ligands, which protect against lung injury by inducing CYP1A enzymes; and (iii) exacerbating enhanced formation of ROS-mediated oxidative DNA adducts derived from 8- 5'cyclopurines or lipid peroxidation products, resulting in oxygen-mediated injury. We propose the following Specific Aims. 1. To test the hypothesis mice lacking the gene for Cyp1b1 will be less susceptible to oxygen injury than wild type mice, and that the beneficial effects of Cyp1b1 deletion is augmented by pre-treatment of the mice with the CYP1A/1B inducer, 2-naphthoflavone (BNF) prior to hyperoxic exposures. 2. To test the hypothesis that Cyp1b1-deletion in pulmonary endothelial cells or Clara cells will result in differential susceptibilities to oxygen-mediated lung injury. The specific hypothesis to be tested is that conditional deletion of Cyp1b1 will offer mechanistic information regarding the specific lung cell types that contribute to the protection against hyperoxic lung injury. 3. To test the hypothesis that oxidative DNA adducts contributes mechanistically to lung injury mediated by hyperoxia, and that these adducts will serve as novel biomarkers of hyperoxic lung injury and BPD. The hypothesis to be tested is that lungs of hyperoxic mice deficient in CYP1B1 will display lesser oxidative DNA damage than WT mice, and augmented expression of CYP1A enzymes in the Cyp1b1-null mouse in part contributes to the amelioration of oxidative DNA damage in the Cyp1b1-null mouse. The hypothesis that cyclopurine dinucleotides, i.e. AcA or GcA, or direct adducts resulting from F2-isoprostanes will serve as early biomarkers of BPD will be tested. We will also test the hypothesis that genetic polymorphisms in CYP1B1 are risk factors for the development of BPD in infants. The proposed studies should help in the development of novel strategies for the prevention/treatment of lung diseases (e.g. BPD and ARDS) in humans. Should CYP1B1 play a pro-oxidant roie in hyperoxic lung injury, then CYP1B1 inhibitors could be developed as potential preventive/therapeutic candidates against BPD and other lung diseases mediated by supplemental oxygen (e.g. ARDS) in humans. These studies are also applicable to ROS-mediated disorders caused by environmental chemicals.

描述（由申请方提供）：高氧通常用于治疗早产儿和足月儿的呼吸窘迫和肺功能不全。然而，过量的氧气有助于慢性肺病（CLD）的发展，也称为支气管肺发育不良（BPD）。高氧介导的肺损伤的分子机制尚不清楚，但活性氧（ROS），这也是由环境化学品产生的，是最有可能的候选者。所提出的研究的中心假设是，肺细胞色素P450（CYP）1B 1通过以下方式在高氧肺损伤中起关键作用：（i）作为促氧化剂，导致脂质过氧化产物（例如，F2-异前列烷，异呋喃），其继而介导肺损伤;（ii）使新的内源性AHR配体失活，其通过诱导CYP 1A酶来保护免受肺损伤;和（iii）加剧ROS介导的衍生自8- 5 '环嘌呤或脂质过氧化产物的氧化DNA加合物的增强形成，导致氧介导的损伤。我们提出以下具体目标。1.为了验证以下假设：缺乏Cyp 1b 1基因的小鼠对氧损伤的敏感性低于野生型小鼠，并且在高氧暴露前用CYP 1A/1B诱导剂2-萘酚酮（BNF）预处理小鼠可增强Cyp 1b 1缺失的有益作用。2.为了检验肺内皮细胞或Clara细胞中Cyp 1b 1缺失将导致对氧介导的肺损伤的不同易感性的假设。待检验的特定假设是Cyp 1b 1的条件性缺失将提供关于有助于保护免受高氧肺损伤的特定肺细胞类型的机制信息。3.为了验证氧化性DNA加合物在高氧介导的肺损伤中起作用的机制，以及这些加合物将作为高氧肺损伤和BPD的新生物标志物的假设。待检验的假设是，CYP 1B 1缺陷的高氧小鼠的肺将显示出比WT小鼠更少的氧化DNA损伤，并且Cyp 1b 1缺失小鼠中CYP 1A酶的表达增加部分地有助于Cyp 1b 1缺失小鼠中氧化DNA损伤的改善。将检验环嘌呤二核苷酸（即AcA或GcA）或由F2-异前列烷产生的直接加合物将作为BPD的早期生物标志物的假设。我们还将检验CYP 1B 1基因多态性是婴儿BPD发生的危险因素这一假设。拟议的研究应有助于开发预防/治疗人类肺部疾病（如BPD和ARDS）的新策略。如果CYP 1B 1在高氧肺损伤中发挥促氧化作用，那么CYP 1B 1抑制剂可以被开发为针对BPD和人类中由补充氧介导的其他肺部疾病（例如ARDS）的潜在预防/治疗候选物。这些研究也适用于由环境化学品引起的ROS介导的疾病。