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: 8391741
• 负责人: BHAGAVATULA MOORTHY
• 金额: $ 41.19万
• 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/8391741
• 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（由申请人提供）：高氧通常用于治疗早产儿和足月婴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，这也被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，但同样由环境化学物质产生的活性氧（ROS）是最有可能的候选者。提出的研究的中心假设是，肺细胞色素P450 (CYP)1B1在高氧肺损伤中发挥关键作用：(i)作为一种促氧化剂，导致脂质过氧化产物（如f2 -异前列腺素，异脲类）的形成增强，从而介导肺损伤；（ii）使新的内源性AHR配体失活，该配体通过诱导CYP1A酶来保护肺免受损伤；（iii）加剧由8- 5'环嘌呤或脂质过氧化产物衍生的ros介导的氧化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：为了验证这一假设，缺乏Cyp1b1基因的小鼠比野生型小鼠更不容易受到氧损伤，并且在高氧暴露之前用CYP1A/1B诱诱剂2-萘黄酮（BNF）预处理小鼠，可以增强Cyp1b1缺失的有益作用。2. 验证肺内皮细胞或Clara细胞cyp1b1缺失对氧介导肺损伤的易感性差异的假设。需要验证的具体假设是，Cyp1b1的条件缺失将提供有关特定肺细胞类型的机制信息，这些细胞类型有助于防止高氧肺损伤。3. 为了验证氧化DNA加合物对高氧肺损伤的机制作用，以及这些加合物将作为高氧肺损伤和BPD的新生物标志物。需要验证的假设是，CYP1B1缺失的高氧小鼠的肺比WT小鼠显示更小的氧化DNA损伤，CYP1B1缺失小鼠中CYP1A酶表达的增强部分有助于改善CYP1B1缺失小鼠的氧化DNA损伤。环嘌呤二核苷酸，即AcA或GcA，或由f2 -异前列腺素产生的直接加合物将作为BPD的早期生物标志物的假设将被测试。我们还将验证CYP1B1基因多态性是婴儿BPD发生的危险因素的假设。拟议的研究应有助于制定预防/治疗人类肺部疾病（如BPD和ARDS）的新策略。如果CYP1B1在高氧性肺损伤中发挥促氧化作用，那么CYP1B1抑制剂可以作为潜在的预防/治疗候选药物，用于治疗BPD和其他由补氧介导的人类肺部疾病（如ARDS）。这些研究也适用于由环境化学物质引起的ros介导的疾病。