title: NF-kappaB Signaling in Chronic Inflammatory Airway Disease.
abstract: Asthma and chronic obstructive pulmonary disease (COPD) are obstructive airway disorders which differ in their underlying causes and phenotypes but overlap in patterns of pharmacological treatments. In both asthma and COPD, oxidative stress contributes to airway inflammation by inducing inflammatory gene expression. The redox-sensitive transcription factor, nuclear factor (NF)-kappaB (NF-κB), is an important participant in a broad spectrum of inflammatory networks that regulate cytokine activity in airway pathology. The anti-inflammatory actions of glucocorticoids (GCs), a mainstay treatment for asthma, involve inhibition of NF-κB induced gene transcription. Ligand bound GC receptors (GRs) bind NF-κB to suppress the transcription of NF-κB responsive genes (i.e., transrepression). However, in severe asthma and COPD, the transrepression of NF-κB by GCs is negated as a consequence of post-translational changes to GR and histones involved in chromatin remodeling. Therapeutics which target NF-κB activation, including inhibitors of IκB kinases (IKKs) are potential treatments for asthma and COPD. Furthermore, reversing GR/histone acetylation shows promise as a strategy to treat steroid refractory airway disease by augmenting NF-κB transrepression. This review examines NF-κB signaling in airway inflammation and its potential as target for treatment of asthma and COPD.
authors.affiliation: Lung Health Research Centre (LHRC), Department Pharmacology and Therapeutics, University of Melbourne, Grattan St., Parkville 3010, Victoria, Australia. schuliga@unimelb.edu.au.
authors.forename: Michael
authors.initials: M
authors.lastname: Schuliga
mesh_terms: D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D012137:Respiratory System / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; D016328:NF-kappa B
keywords: airway smooth muscle; allergic asthma; alveolar macrophages; cigarette smoke; emphysema; eosinophils; epithelium; histone deacetylase; phosphoinositide 3 kinase-delta (PI3K-δ); sirtuins