Nuclear factor kappa B is a promising therapeutic target in inflammatory lung disease.
Nuclear factor kappa B (NF-kappaB) 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-kappaB pathway. The basic molecular biology of the NF-kappaB 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 IkappaB. 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-kappaB binding and inhibition of gene expression, respectively, of NF-kappaB 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-kappaB activation pathway and amenable to conventional small molecule pharmaceutical approaches.
Park
Gye Young
GY
Department of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois, 840 S. Wood St. Chicago IL 60612, USA.
Christman
John W
JW
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000187:drug effects; D011014:Pneumonia / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D004791:Enzyme Inhibitors; D016328:NF-kappa B; D051550:I-kappa B Kinase