Oxidants have been implicated in the pathogenesis of a number of diseases and biological processes including atherosclerosis, carcinogenesis, and inflammatory disorders. Oxidants can cause cellular damage in the lung by oxidizing nucleic acids, proteins, and membrane lipids. Hyperoxia (>95 percent oxygen) can lead to inflammation and extensive impairment of respiratory function. Sufficiently long hyperoxia exposure (>3 days) is lethal. Understanding those factors that confer differential susceptibility to hyperoxic lung injury should lead to improved strategies to prevent or lessen the injury due to oxidants. Inter-species and inter-strain differences in hyperoxia-induced lung injury suggests that genetic background is an important risk factor. Among inbred mice, the C57BL/6J(B6) strain has greater responses to hyperoxia challenge than C3H/HeJ(C3). Linkage analyses have identified significant and suggestive susceptibility quantitative trait loci (QTLs) on chromosomes 2 and 3, respectively. The chromosone 2 QTL contains a strong candidate susceptibility gene, NF-E2 related factor 2 (Nrf2), which encodes an essential nuclear transcription factor (NRF-2) involved in antioxidant gene expression and regulation. Initial experimental results are consistent with a strong role for this gene in differential susceptibility to hyperoxic lkung injury. OVERALL OBJECTIVE. The overall objective of this proposal is to determine the mechanisms through which Nrf2 confers differential susceptibility to hyperoxic lung injury in inbred mice. SPECIFIC OBJECTIVES. We have designed three Specific Aims.
In Aim 1, we will determine the mechanisms through which Nrf2 expression is regulated in response to continuous hyperoxia exposure.
In Aim 2, we will utilize gene targeting and overexpression to address in vivo and in vitro the functional role of Nrf2 in the pathogenesis of hyperoxic lung injury.
In Aim 3, we will determine the effector mechanisms of Nrf2 activation in differentially hyperoxia-susceptible inbred strains of mice.

Public Health Relevance

. This proposal utilizes a multi-disciplinary approach that will provide unique insight into the genetic mechanisms that determine differential susceptibility to hyperoxia-induced lung injury. Inasmuch as there is close homology between the mouse and human genomes, the identification and characterization of genes that control susceptibility to hyperoxia in this model may provide a means to characterize individuals in human populations who are at risk to oxidant lung injury, and a strategy for intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066109-04
Application #
6696600
Study Section
Special Emphasis Panel (ZRG1-ALTX-1 (01))
Program Officer
Harabin, Andrea L
Project Start
2001-02-01
Project End
2006-12-31
Budget Start
2004-01-01
Budget End
2006-12-31
Support Year
4
Fiscal Year
2004
Total Cost
$367,875
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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-?B-Dependent, LPS-Stimulated Fos-Related Antigen-1 Transcription in Alveolar Macrophages. Am J Respir Cell Mol Biol 55:667-674
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
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
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; 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
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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