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.

Public Health Relevance

Hyperoxia is routinely used in the treatment of respiratory distress and pulmonary insufficiency in preterm and term infants, and in adults with ARDS. However, hyperoxia contributes to the development of chronic lung disease (CLD), also known as bronchopulmonary dysplasia (BPD). This project is aimed at developing novel strategies for the prevention/treatment of lung diseases such as BPD and ARDS in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES019689-04
Application #
8586889
Study Section
Special Emphasis Panel (ZRG1-DKUS-D (02))
Program Officer
Nadadur, Srikanth
Project Start
2010-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$378,076
Indirect Cost
$109,651
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Mallick, Pankajini; Basu, Sumit; Moorthy, Bhagavtula et al. (2017) Role of Toll-like receptor 4 in drug-drug interaction between paclitaxel and irinotecan in vitro. Toxicol In Vitro 41:75-82
Lingappan, Krithika; Maity, Suman; Jiang, Weiwu et al. (2017) Role of Cytochrome P450 (CYP)1A in Hyperoxic Lung Injury: Analysis of the Transcriptome and Proteome. Sci Rep 7:642
Shrestha, Amrit Kumar; Patel, Ananddeep; Menon, Renuka T et al. (2017) Leflunomide induces NAD(P)H quinone dehydrogenase 1 enzyme via the aryl hydrocarbon receptor in neonatal mice. Biochem Biophys Res Commun 485:195-200
Mallick, Pankajini; Taneja, Guncha; Moorthy, Bhagavatula et al. (2017) Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics-small molecule drug interactions. Expert Opin Drug Metab Toxicol 13:605-616
Dinu, Daniela; Chu, Chun; Veith, Alex et al. (2016) Mechanistic role of cytochrome P450 (CYP)1B1 in oxygen-mediated toxicity in pulmonary cells: A novel target for prevention of hyperoxic lung injury. Biochem Biophys Res Commun 476:346-351
Lingappan, Krithika; Jiang, Weiwu; Wang, Lihua et al. (2016) Sex-specific differences in neonatal hyperoxic lung injury. Am J Physiol Lung Cell Mol Physiol 311:L481-93
Ghose, Romi; Mallick, Pankajini; Taneja, Guncha et al. (2016) In Vitro Approaches to Study Regulation of Hepatic Cytochrome P450 (CYP) 3A Expression by Paclitaxel and Rifampicin. Methods Mol Biol 1395:55-68
Shivanna, Binoy; Maity, Suman; Zhang, Shaojie et al. (2016) Gene Expression Profiling Identifies Cell Proliferation and Inflammation as the Predominant Pathways Regulated by Aryl Hydrocarbon Receptor in Primary Human Fetal Lung Cells Exposed to Hyperoxia. Toxicol Sci 152:155-68
Shah, Pranav; Omoluabi, Ozozoma; Moorthy, Bhagavatula et al. (2016) Role of Adaptor Protein Toll-Like Interleukin Domain Containing Adaptor Inducing Interferon ? in Toll-Like Receptor 3- and 4-Mediated Regulation of Hepatic Drug Metabolizing Enzyme and Transporter Genes. Drug Metab Dispos 44:61-7
Patel, Ananddeep; Zhang, Shaojie; Shrestha, Amrit Kumar et al. (2016) Omeprazole induces heme oxygenase-1 in fetal human pulmonary microvascular endothelial cells via hydrogen peroxide-independent Nrf2 signaling pathway. Toxicol Appl Pharmacol 311:26-33

Showing the most recent 10 out of 37 publications