Many patients with pulmonary diseases, such as acute respiratory distress syndrome and emphysema, require hyperoxia to maintain adequate tissue oxygenation. However, hyperoxia although beneficial can further perpetuate/exacerbate acute lung injury (ALI). Through a genetic linkage analysis, we have first identified Nrf2 transcription factor as an important candidate gene that regulates hyperoxic lung injury (HLI). The overall objective of the previous proposal was to examine the role of Nrf2 and its downstream target genes involved in HLI. During the last funding period, we have shown that Nrf2-deficient (Nrf2-/-) mice have a greater susceptibility to hyperoxia induced lung injury and inflammatory responses, compared with wildtype (Nrf2+/+) mice. This was primarily due to a diminished lower level of both basal and inducible expression of antioxidant enzymes (AOEs), which are critical to detoxify reactive oxygen (ROS) and/or nitrogen (RNS) species, in Nrf2-/- mice. Genetic variations appear to play a significant role in modulating the development of complex disorders such as ALI. Since NRF2 is a master regulator of cellular oxidative stress, a major determinant that can contribute to ALI, we have analyzed polymorphisms in the coding and non-coding regions of NRF2 gene. To this end, we found novel functional single nucleotide polymorphisms (SNPs) in the promoter region of NRF2 that were associated with at-risk patients with major trauma. Thus, our preliminary findings provide an important framework for expanding the scope of this project to determine the functional relevance of NRF2 promoter polymorphisms. We hypothesize that perturbation either in specific signaling or factors controlling the NRF2 expression and activation may result in lower levels of antioxidant enzyme expression, thereby contributing to or enhancing susceptibility to the development of respiratory pathogenesis. To test our hypothesis, we propose the following four Specific Aims: 1) To determine the functional importance of novel SNPs in regulation of NRF2 transcription. 2) To Identify the trans-factor(s) that modulate NRF2 transcription and determine whether or not the binding of these transcriptional factors to the NRF2 promoter is altered by hyperoxia and relevant to the SNPs. 3) Elucidate the signal transduction pathways that lead to NRF2 dissociation from the NRF2:KEAP1 complex in response to acute and chronic hyperoxia exposure in vitro. 4) Investigate whether PI3K-Akt signaling via Nrf2 regulates HLI and whether boosting antioxidant gene expression by activating Nrf2 using a synthetic triterpenoid, which work at very low doses, will confer protection against HLI in mice. Our overall findings may have important implications to identify the effector mechanisms causing susceptibility to ALI and may be helpful to modulate the development of this complex disorder and other respiratory diseases that have been linked to oxidant stress. In addition, the results of this study will provide a strong rationale to further explore the use of this triterpenoid as potential therapeutic agents in modulating HLI. NRF2-dependent transcriptional response is vital to mitigate cellular stress induced by various oxidants and toxicants, our overall findings may have important implications to identify the effector mechanisms causing susceptibility to acute lung injury and may be helpful to modulate development of this complex disorder and other respiratory diseases that have been linked to oxidant stress.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Harabin, Andrea L
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University of Illinois at Chicago
Schools of Medicine
United States
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Potteti, Haranatha R; Rajasekaran, Subbiah; Rajamohan, Senthilkumar B et al. (2016) Sirtuin 1 Promotes Hyperoxia-Induced Lung Epithelial Cell Death Independent of NF-E2-Related Factor 2 Activation. Am J Respir Cell Mol Biol 54:697-706
Mishra, Rakesh K; Potteti, Haranatha R; Tamatam, Chandramohan R et al. (2016) c-Jun Is Required for Nuclear Factor-κB-Dependent, LPS-Stimulated Fos-Related Antigen-1 Transcription in Alveolar Macrophages. Am J Respir Cell Mol Biol 55:667-674
Jain, Atul D; Potteti, Haranatha; Richardson, Benjamin G et al. (2015) Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators. Eur J Med Chem 103:252-68
Vaz, Michelle; Rajasekaran, Subbiah; Potteti, Haranatha R et al. (2015) Myeloid-specific Fos-related antigen-1 regulates cigarette smoke-induced lung inflammation, not emphysema, in mice. Am J Respir Cell Mol Biol 53:125-34
Reddy, Narsa M; Potteti, Haranatha R; Vegiraju, Suryanarayana et al. (2015) PI3K-AKT Signaling via Nrf2 Protects against Hyperoxia-Induced Acute Lung Injury, but Promotes Inflammation Post-Injury Independent of Nrf2 in Mice. PLoS One 10:e0129676
Mezu-Ndubuisi, Olachi J; Wanek, Justin; Chau, Felix Y et al. (2014) Correspondence of retinal thinning and vasculopathy in mice with oxygen-induced retinopathy. Exp Eye Res 122:119-22
Liu, Manchang; Reddy, Narsa M; Higbee, Elizabeth M et al. (2014) The Nrf2 triterpenoid activator, CDDO-imidazolide, protects kidneys from ischemia-reperfusion injury in mice. Kidney Int 85:134-41
Mittal, Manish; Siddiqui, Mohammad Rizwan; Tran, Khiem et al. (2014) Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 20:1126-67
Mezu-Ndubuisi, Olachi J; Teng, Pang-yu; Wanek, Justin et al. (2013) In vivo retinal vascular oxygen tension imaging and fluorescein angiography in the mouse model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 54:6968-72
Huang, Long Shuang; Berdyshev, Evgeny; Mathew, Biji et al. (2013) Targeting sphingosine kinase 1 attenuates bleomycin-induced pulmonary fibrosis. FASEB J 27:1749-60

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