RT Journal Article
SR Electronic
T1 Oxidative stress and redox regulation of lung inflammation in COPD
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 219
OP 242
DO 10.1183/09031936.06.00053805
VO 28
IS 1
A1 I. Rahman
A1 I. M. Adcock
YR 2006
UL http://erj.ersjournals.com/content/28/1/219.abstract
AB Reactive oxygen species, either directly or via the formation of lipid peroxidation products, may play a role in enhancing inflammation through the activation of stress kinases (c-Jun activated kinase, extracellular signal-regulated kinase, p38) and redox-sensitive transcription factors, such as nuclear factor (NF)-κB and activator protein-1. This results in increased expression of a battery of distinct pro-inflammatory mediators. Oxidative stress activates NF-κB-mediated transcription of pro-inflammatory mediators either through activation of its activating inhibitor of κB-α kinase or the enhanced recruitment and activation of transcriptional co-activators. Enhanced NF-κB-co-activator complex formation results in targeted increases in histone modifications, such as acetylation leading to inflammatory gene expression. Emerging evidence suggests the glutathione redox couple may entail dynamic regulation of protein function by reversible disulphide bond formation on kinases, phosphatases and transcription factors. Oxidative stress also inhibits histone deacetylase activity and in doing so further enhances inflammatory gene expression and may attenuate glucocorticoid sensitivity. The antioxidant/anti-inflammatory effects of thiol molecules (glutathione, N-acetyl-L-cysteine and N-acystelyn, erdosteine), dietary polyphenols (curcumin-diferuloylmethane, cathechins/quercetin and reserveratol), specific spin traps, such as α-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (extracellular superoxide dismutase (SOD) mimetic, SOD mimetic M40419 and SOD, and catalase manganic salen compound, eukarion-8), porphyrins (AEOL 10150 and AEOL 10113) and theophylline have all been shown to play a role in either controlling NF-κB activation or affecting histone modifications with subsequent effects on inflammatory gene expression in lung epithelial cells. Thus, oxidative stress regulates both key signal transduction pathways and histone modifications involved in lung inflammation. Various approaches to enhance lung antioxidant capacity and clinical trials of antioxidant compounds in chronic obstructive pulmonary disease are also discussed. SERIES “SIGNALLING AND TRANSCRIPTIONAL REGULATION IN INFLAMMATORY AND IMMUNE CELLS: IMPORTANCE IN LUNG BIOLOGY AND DISEASE” Edited by K.F. Chung and I.M. Adcock Number 6 in this Series