The pathogenic progression of acute lung injury (ALI) involves airway inflammation, epithelial injury, and the impairment of gas exchange. Despite concerted public health efforts, no effective therapy exists to prevent ALI and mortality remains >30%. S-nitrosothiols (SNOs) are endogenous molecules produced by the respiratory epithelium that are found in high concentration in the lung. SNOs serve an anti-inflammatory role by inhibiting activation of immune response pathways, including NF-kB. SNOs inhibit NF-kB by targeting the p65 subunit of the activating heterodimer (p50-p65) for S-nitrosylation. Using a mouse LPS model, we have shown that lung SNOs are depleted early in the course of ALI which occurs in conjunction with p65 denitrosylation, NF-kB activation, and airway inflammation. Augmenting lung SNOs prevents lung inflammation/injury by inhibiting NF-kB denitrosylation, emphasizing the pathophysiological importance of this mechanism. Recently, we have shown cytokines similarly induce p65 denitrosylation in the respiratory epithelium with this process regulated by thioredoxin (Trx). Trx inhibitors prevent p65 denitrosylation, NF-kB activation, and cytokine expression in the ALI model, suggesting Trx to be the mediator of SNO depletion. These data support our hypothesis that SNO depletion is a critical factor in ALI pathogenesis. To test this hypothesis, we formulated the following aims: 1. Determine if Trx regulates lung SNO metabolism and initiates the inflammatory response in ALI. 2. Determine if lung SNO augmentation inhibits the development of pneumonia- and sepsis-related ALI. 3. Quantify airway SNOs in ALI/ARDS patients and correlate with disease severity/outcomes. We anticipate that completion of the proposed aims will provide the translational data that is essential to support the clinical testing of airway SNO repletion as treatment for the prevention and development of ALI.

Public Health Relevance

Acute lung injury or adult respiratory distress syndrome (ARDS) is a disease with an annual incidence in the United States of approximately 190,000 cases and a mortality rate between 40-50%. Despite its clinical significance, the pathophysiology of acute lung injury remains poorly understood with treatment limited to supportive care. This research project will address the importance of endogenously-produced molecules termed S-nitrosothiols, in controlling the inflammation that is associated with acute lung injury. The knowledge gained from the proposed studies could lead to the development of new therapies that target inflammation in acute lung injury and other pulmonary disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL092994-05
Application #
8759365
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2008-07-01
Project End
2018-04-30
Budget Start
2014-09-05
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
$392,500
Indirect Cost
$142,500
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Kelleher, Zachary T; Sha, Yonggang; Foster, Matthew W et al. (2014) Thioredoxin-mediated denitrosylation regulates cytokine-induced nuclear factor *B (NF-*B) activation. J Biol Chem 289:3066-72
Foster, Matthew W; Thompson, J Will; Forrester, Michael T et al. (2013) Proteomic analysis of the NOS2 interactome in human airway epithelial cells. Nitric Oxide 34:37-46
Kelleher, Zachary T; Potts, Erin N; Brahmajothi, Mulugu V et al. (2011) NOS2 regulation of LPS-induced airway inflammation via S-nitrosylation of NF-{kappa}B p65. Am J Physiol Lung Cell Mol Physiol 301:L327-33
Forrester, Michael T; Seth, Divya; Hausladen, Alfred et al. (2009) Thioredoxin-interacting protein (Txnip) is a feedback regulator of S-nitrosylation. J Biol Chem 284:36160-6
Marshall, Harvey E; Potts, Erin N; Kelleher, Zachary T et al. (2009) Protection from lipopolysaccharide-induced lung injury by augmentation of airway S-nitrosothiols. Am J Respir Crit Care Med 180:11-8