Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by an initial airway inflammatory insult that results in diffuse alveolar damage and the subsequent development of respiratory failure. Despite an incidence of ~200,000 cases/year in the United States and mortality rate approaching 40%, no effective therapy exists to treat ALI/ARDS. S-nitrosothiols (SNOs) are endogenously-produced, bioactive forms of nitric oxide that function to inhibit immune response pathways in the respiratory epithelium. Recently, we demonstrated that airway SNOs are acutely depleted in a mouse model of ALI and that treatment with inhaled ethyl nitrite (ENO), an S-nitrosylating agent, protects from the development of lung injury. However, the molecular targets of SNOs in the lung airway remain to be discerned. We hypothesize that proteomic signatures derived from analysis of airway lining fluid can be used to elucidate the SNO-regulated immune response pathways in ALI which underlie the pharmacological basis of ENO therapy. Accordingly, we propose to: 1. Characterize the effects of ENO treatment on the airway proteome in ALI and identify signaling pathways that are affected by SNO repletion;and 2. Identify BALF proteins that are modified by S- nitrosylation in ALI and determine the effects of S-nitrosylation on their inflammatory activities.. Completion of these specific aims should provide a fuller understanding of SNO-regulated pathways in the airways and will guide the further study of SNO-based therapy for the prevention and resolution of inflammatory lung injury.

Public Health Relevance

Ethyl nitrite (ENO), a gaseous S-nitrosylating agent, is protective in animal models of acute lung injury. We will determine the molecular targets of ENO therapy by quantifying gene and protein level changes, as well as protein S-nitrosylation, in the airways of ENO-treated mice

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL106121-01
Application #
8030572
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2010-12-01
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
1
Fiscal Year
2011
Total Cost
$196,250
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Kelleher, Zachary T; Sha, Yonggang; Foster, Matthew W et al. (2014) Thioredoxin-mediated denitrosylation regulates cytokine-induced nuclear factor κB (NF-κB) activation. J Biol Chem 289:3066-72
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Foster, Matthew W (2012) Methodologies for the characterization, identification and quantification of S-nitrosylated proteins. Biochim Biophys Acta 1820:675-83
Foster, Matthew W; Yang, Zhonghui; Gooden, David M et al. (2012) Proteomic characterization of the cellular response to nitrosative stress mediated by s-nitrosoglutathione reductase inhibition. J Proteome Res 11:2480-91
Marshall, Harvey E; Foster, Matthew W (2012) S-nitrosylation of Ras in breast cancer. Breast Cancer Res 14:113