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.
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