The NF-kappaB transcription factor family affects gene expression of pro-inflammatory cytokines, chemokines, adhesion molecules, and enzymes. Signal transduction pathways initiated by ligand binding to toll-like receptors, IL-1 receptor, and TNF type 1 receptor lead to activation of NF-kappaB, implicating NF-kappaB as a critical integrator of inflammatory signals. While innate immune responses are necessary for effective lung host defense, dysfunctional or exaggerated inflammatory responses lead to lung injury. Although NF-kappaB activation appears to be necessary for generation of lung inflammation by bacterial lipopolysaccharide, it is currently, uncertain whether specific parameters of NF-kappaB activation determine of the severity of lung inflammation and injury. We hypothesize that acute lung injury results from a dysfunctional innate immune response characterized by NF-kappaB activation in the lungs that is exaggerated in degree, distribution, or duration. We have 3 specific aims to test this hypothesis using mouse models of lung inflammation and injury induced by E. coli lipopolysaccharide: 1) to define the degree, distribution, and duration of NF-kappaB activation in individual lung cell types in models of mild and severe lung inflammation and injury, 2) to determine the specific role of the NF-kappaB pathway in lung macrophages and immigrating neutrophils in regulating lung inflammation and injury, and 3) to examine the effects of selective NF-kappaB activation or inhibition in airway epithelium on lung inflammation and injury. Defining the relationships between NF-kappaB activation in specific cell types, production of NF-kappaB linked inflammatory mediators, lung inflammation, and lung injury are crucial to understanding the pathobiology of a variety of human lung diseases, including the acute respiratory distress syndrome, where minimizing lung injury is an important goal of treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061419-08
Application #
7073440
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Harabin, Andrea L
Project Start
1999-01-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2008-05-31
Support Year
8
Fiscal Year
2006
Total Cost
$221,177
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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