Pulmonary emphysema, a devastating disease associated with chronic exposure to cigarette smoke (CS) and environmental pollutants, is characterized by abnormal inflammation, air space enlargement, and the loss of alveolar structures. Other than congenital genetic deficiencies (which contribute to less than 5% of cases), the genes that determine susceptibility to emphysema are unknown. Our goal is to elucidate genes and pathways that can act as """"""""risk modifiers"""""""" for emphysema. Our preliminary studies have shown that redox-sensitive bZIP transcription factor NF-E2 related factor 2 (Nrf2), which regulates antioxidant pathways, could be an important modifier gene for CS-emphysema. Disruption of the nrf2 gene (in the emphysema-resistant ICR strain) results in early onset and severe CS-emphysema. In response to CS, the lungs of Nrf2-/-mice have enhanced oxidative stress and apoptosis, increased alveolar inflammation, and loss of alveolar structures. We hypothesize that Nrf2 plays a central role in preservation of alveolar structures by maintaining the balances of pulmonary oxidants/antioxidants and proteinases/antiproteinases during CS exposure. Reduced or absent Nrf2 response causes imbalances that lead to early and severe emphysema. We will test this hypothesis by comparing mice with high Nrf2 response (ICR), low Nrf2 response (C57BL/6J Nrf2+/+) and no Nrf2 response (C57BL/6J Nrf2 -/-).
Our aims are (1) To determine the relationship between Nrf2 response and preservation of lung structure in the CS-emphysema mouse model. (2) To investigate the Nrf2-mediated oxidant/antioxidant balance in inhibition of CS-emphysema. (3) To determine the mechanism by which Nrf 2 response inhibits emphysema by maintaining the proteinase/antiproteinase balance. (4) To test if overexpression of Nrf2 can inhibit emphysema. These studies promise to shed new light on novel pathways that modulate susceptibility to emphysema.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL081205-01
Application #
6957095
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Croxton, Thomas
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$407,500
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
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