Supplemental oxygen is frequently used in the treatment of pulmonary insufficiency in patients with acute respiratory distress syndrome (ARDS), which is a severe form of acute lung injury (ALI), affecting millions worldwide. Hyperoxic lung injury is recognized as an appropriate model for ALI/ARDS. The central hypothesis of the research proposed in this application is that specific single nucleotide polymorphisms (SNPs) in the genes for NF-E2-related factor (Nrf2) and/or NADPH quinone reductase (NQO1) contribute to ALI/ARDS by attenuating the expression of pulmonary and hepatic functional phase II anti-oxidant enzymes, leading to increased formation of oxygen-mediated reactive oxygen species (ROS), which in turn results in increased susceptibility to ALI/ARDS, as well as exacerbated lung damage in these patients. In order to achieve these goals, we propose the following Specific Aims: 1. To test the hypothesis that humans carrying specific SNPs on the Nrf2 or NQO1 genes will be more susceptible to develop ALI/ARDS than those who do not, and these individuals will display increased sensitivity to oxidative stress than those carrying the wild type genes. Endotracheal aspirates from individuals suffering from ALI/ARDS or controls will be analyzed for the presence of SNPs, F2- isoprostanes/isofurans, levels of bulky oxidative DNA adducts, and protein oxidation products. Gene expression profiles will also be studied using RNA from tracheal aspirates of these individuals. 2. To determine the mechanisms by which mice lacking the genes for Nrf2 and NQO1 are more susceptible to hyperoxic lung injury, and test the hypothesis that the cytochrome P4501A (CYP1A) inducer [e.g., ?- napthoflavone (BNF)] or omeprazole (OM) will rescue the mice lacking functional Nrf2 or NQO1 genes against hyperoxic lung injury, via novel mechanisms entailing hepatic and pulmonary CYP1A enzymes. 3. To determine the mechanisms by which known SNPs on the Nrf2 or NQO1 promoter modulate oxygen toxicity in human lung cells or in humanized mice in vivo.
This aim has two sub-aims. (i). To test the hypothesis that human lung cells carrying known SNPs of Nrf2 or NQO1 gene will be more susceptible to oxygen toxicity. (ii) To create transgenic humanized mice expressing the normal human Nrf2 gene or NQO1 gene or those carrying known SNPs on these genes, and determine the role of SNPs in hyperoxic lung injury. Omics'approaches, including genomics (microarrays) and proteomics approaches will be used to determine the molecular mechanisms by which Nrf2 or NQO1 variants contribute to lung injury. Successful accomplishment of the aims could lead to innovative strategies for the development of novel biomarkers as well as new approaches (e.g., use of PPI such as OM) for the prevention/treatment of ALI/ARDS in humans.
This project is aimed at determining the mechanisms by which these genetic variants of NF-E2-related factor (Nrf2) and/or NADPH quinone reductase (NQO1) genes contribute to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in humans. Successful accomplishment of the aims could lead to innovative strategies for the development of novel biomarkers as well as novel approaches for the prevention/treatment of ALI/ARDS in humans.
|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|
|Shivanna, Binoy; Zhang, Wenyan; Jiang, Weiwu et al. (2013) Functional deficiency of aryl hydrocarbon receptor augments oxygen toxicity-induced alveolar simplification in newborn mice. Toxicol Appl Pharmacol 267:209-17|