Oxidative stress and gene transcription in asthma and chronic obstructive pulmonary disease: antioxidant therapeutic targets.
Inflammatory lung diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD) are characterised by systemic and local chronic inflammation and oxidative stress. The sources of the increased oxidative stress in patients with asthma and COPD derive from the increased burden of inhaled oxidants, and from the increased amounts of reactive oxygen species (ROS) generated by several inflammatory, immune and structural cells of the airways. Increased levels of ROS produced in the airways are reflected by increased markers of oxidative stress in the airspaces, sputum, breath, lungs and blood in patients with asthma and COPD. ROS, either directly or via the formation of lipid peroxidation products such as acrolein, 4-hydroxy-2-nonenal and F(2)-isoprostanes, may play a role in enhancing the inflammation through the activation of stress kinases (JNK, MAPK, p38, phosphoinositide 3 (PI-3)-kinase/PI-3K-activated serine-threonine kinase Akt) and redox sensitive transcription factors such as NF-kappaB and AP-1. Recent data have also indicated that oxidative stress and pro-inflammatory mediators can alter nuclear histone acetylation/deacetylation allowing access for transcription factor DNA binding leading to enhanced pro-inflammatory gene expression in various lung cells. Furthermore, oxidative stress may alter the balance between gene expression of pro-inflammatory mediators and antioxidant enzymes in favor of inflammatory mediators in the lung. Thus, the presence of oxidative stress may have important consequences for the pathogenesis of asthma and COPD. Identification of genes that predispose to the development of asthma and COPD may identify novel therapeutic targets. Future work is directed to understand the molecular mechanisms of antioxidants on ROS-mediated cell signaling pathways and inhibition of inflammatory response that would provide information for the development of novel antioxidant therapeutic targets in asthma and COPD. Effective wide spectrum antioxidant therapy that has good bioavailability and potency is urgently needed to control the localised oxidative and inflammatory processes that occur in the pathogenesis of asthma and COPD. In addition, development of such novel antioxidant compounds would be therapeutically useful in monitoring the oxidative and inflammatory biomarkers in the progression/severity of asthma and COPD.
Rahman
Irfan
I
ELEGI Laboratory, MRC Centre for Inflammation Research, Medical School, University of Edinburgh, Edinburgh, UK. Irfan.Rahman@ed.ac.uk
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D002843:Chromatin / Q000502:physiology; D019175:DNA Methylation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012907:Smoking / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
D000975:Antioxidants; D002843:Chromatin; D006657:Histones; D017382:Reactive Oxygen Species