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Title: The role of the IKK-2/NF-kB signaling in cigarette smoke-induced airway inflammation
Author: Rastrick, Joseph
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory lung disease largely associated with cigarette smoke (CS) exposure. The mechanism by which CS leads to the pathogenesis of COPD remains unclear, however many inflammatory mediators present in the COPD lung are thought to be regulated by the transcription factor Nuclear Factor-kappaB (NF-kB) and its upstream signalling kinase, Inhibitor of kB kinase-2 (IKK-2). The IKK- 2/NF-kB signalling pathway may therefore be crucial in the pathogenesis of the inflammation associated with COPD. To investigate this hypothesis, mice were exposed to acute or sub-chronic CS and inflammatory end-points, including NF-kB pathway activation were measured. Acute CS generated a predominantly neutrophilic response in the lung, whereas the inflammatory phenotype following sub-chronic exposure was more persistent and included monocytes/macrophages and lymphocytes. In contrast to lipopolysaccharide (LPS)-induced lung inflammation however, neither acute nor sub-chronic CS generated an increase in NF-kB:DNA association in whole lung nuclear extracts. To determine if distinct cell types were responsible for a CS-induced change in NF-kB:DNA association, that could not be detected in whole lung nuclear extracts, mice lacking IKK-2 exclusively in the airway epithelium or in myeloid-derived cells were exposed to acute and sub-chronic CS. These mice were shown to have reduced IKK-2 gene expression in the targeted cell types and both strains showed a functional decrease in LPS-induced NF-kB:DNA association. CS-induced lung inflammation however, was not reduced by ablation of IKK-2 in either cell type. This was confirmed using 2 small molecule, structurally distinct 3 IKK-2 specific inhibitors, with proven efficacy against LPS-induced NF-kB:DNA association and neutrophilia. In support of these findings, lung tissue taken from human COPD patients also showed no change in NF-kB:DNA association compared to 'healthy smokers' and non-smokers, leading to the conclusion that contrary to previous reports, NF-kB may not play a prominent role in CS-induced lung inflammation.
Supervisor: Belvisi, Maria ; Birrell, Mark ; Adcock, Ian Sponsor: Medical Research Council ; UCB Celltech
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available