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Nuclear Factor Kappa B is a Promising Therapeutic Target in Inflammatory Lung Disease

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Nuclear factor kappa B (NF-kB) regulates the transcription of a wide array of gene products that are involved in the molecular pathobiology of the lung. Three lung cell types, epithelial cells, macrophages and neutrophils, have been shown to be involved in the generation of lung inflammation through signaling mechanisms that are dependent on activation of the NF-kB pathway. The basic molecular biology of the NF-kB activation pathway is well described, and approaches to modify this axis have involved inhibition of various components of the classical activation pathway, including ubiquitination and proteosomal degradation of IkB. Recently, there have been detailed characterizations of molecular mechanisms that involve reversible post-translational modification of RelA, including phosphorylation and acetylation that might be amenable to therapeutic interdiction. Alternately DNA decoy, antisense and siRNA technologies that interfere with NF-kB binding and inhibition of gene expression, respectively, of NF-kB proteins have been employed in experimental settings, but this has not been practically or effectively applied in human disease. A very promising approach, in our view, is inhibition of inhibitory kappa B kinases (IKK) since these appear to be highly specific for the NF-kB activation pathway and amenable to conventional small molecule pharmaceutical approaches.

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Keywords: inhibitory kappa B kinases (IKK); neutrophils; phosphorylation; posttranslational modification; proinflammatory mediators

Document Type: Research Article

Affiliations: Department of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois, 840 South Wood Street Chicago IL 60612, USA.

Publication date: June 1, 2006

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  • Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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