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
Phillips, Tracie D; Richardson, Molly; Cheng, Yi-Shing Lisa et al. (2015) Mechanistic relationships between hepatic genotoxicity and carcinogenicity in male B6C3F1 mice treated with polycyclic aromatic hydrocarbon mixtures. Arch Toxicol 89:967-77
Thakur, Vijay S; Liang, Yanhong W; Lingappan, Krithika et al. (2014) Increased susceptibility to hyperoxic lung injury and alveolar simplification in newborn rats by prenatal administration of benzo[a]pyrene. Toxicol Lett 230:322-32
Davies, Jonathan; Karmouty-Quintana, Harry; Le, Thuy T et al. (2014) Adenosine promotes vascular barrier function in hyperoxic lung injury. Physiol Rep 2:
Tiwari, Kirti Kumar; Chu, Chun; Couroucli, Xanthi et al. (2014) Differential concentration-specific effects of caffeine on cell viability, oxidative stress, and cell cycle in pulmonary oxygen toxicity in vitro. Biochem Biophys Res Commun 450:1345-50
Lingappan, Krithika; Jiang, Weiwu; Wang, Lihua et al. (2014) Mice deficient in the gene for cytochrome P450 (CYP)1A1 are more susceptible than wild-type to hyperoxic lung injury: evidence for protective role of CYP1A1 against oxidative stress. Toxicol Sci 141:68-77
Lingappan, Krithika; Srinivasan, Chandra; Jiang, Weiwu et al. (2014) Analysis of the transcriptome in hyperoxic lung injury and sex-specific alterations in gene expression. PLoS One 9:e101581
Gandhi, Adarsh; Guo, Tao; Shah, Pranav et al. (2013) Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice. Toxicol Appl Pharmacol 266:430-8
Lingappan, Krithika; Jiang, Weiwu; Wang, Lihua et al. (2013) Sex-specific differences in hyperoxic lung injury in mice: implications for acute and chronic lung disease in humans. Toxicol Appl Pharmacol 272:281-90
Zhou, Guo-Dong; Zhu, Huiping; Phillips, Tracie D et al. (2011) Effects of dietary fish oil on the depletion of carcinogenic PAH-DNA adduct levels in the liver of B6C3F1 mouse. PLoS One 6:e26589
Jiang, Weiwu; Couroucli, Xanthi I; Wang, Lihua et al. (2011) Augmented oxygen-mediated transcriptional activation of cytochrome P450 (CYP)1A expression and increased susceptibilities to hyperoxic lung injury in transgenic mice carrying the human CYP1A1 or mouse 1A2 promoter in vivo. Biochem Biophys Res Commun 407:79-85

Showing the most recent 10 out of 13 publications