Antioxidant therapies in COPD

Abstract

Oxidative stress is an important feature in the pathogenesis of COPD. Targeting oxidative stress with antioxidants or boosting the endogenous levels of antioxidants is likely to be beneficial in the treatment of COPD. Antioxidant agents such as thiol molecules (glutathione and mucolytic drugs, such as N-acetyl-L-cysteine and N-acystelyn), dietary polyphenols (curcumin, resveratrol, green tea, catechins/quercetin), erdosteine, and carbocysteine lysine salt, all have been reported to control nuclear factor-kappaB (NF-kappaB) activation, regulation of glutathione biosynthesis genes, chromatin remodeling, and hence inflammatory gene expression. Specific spin traps such as alpha-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (ECSOD mimetic), porphyrins (AEOL 10150 and AEOL 10113), and a superoxide dismutase mimetic M40419 have also been reported to inhibit cigarette smoke-induced inflammatory responses in vivo. Since a variety of oxidants, free radicals, and aldehydes are implicated in the pathogenesis of COPD, it is possible that therapeutic administration of multiple antioxidants will be effective in the treatment of COPD. Various approaches to enhance lung antioxidant capacity and clinical trials of antioxidant compounds in COPD are discussed.

Figure 1

Mechanism of reactive oxygen species (ROS)-mediated lung inflammation. Inflammatory response is mediated by oxidants inhaled and/or released by the activated neutrophils, alveolar macrophages, eosinophils, and epithelial cells, leading to production of ROS and membrane lipid peroxidation. Activation of transcription of the proinflammatory cytokine and chemokine genes, up-regulation of adhesion molecules, and increased release of proinflammatory mediators are involved in the inflammatory responses in patients with COPD.

Figure 2

Model showing the possible mechanism of histone acetylation by oxidative stress and its repression by corticosteroids (GCs), leading to inhibition of gene transcription. Mitogen-activating protein kinase (MAPK) signaling pathways may be activated by oxidative stress, leading to histone acetylation. Direct interaction between co-activators (HAT), histone deacetylase (HDAC), and the glucocorticoid receptor (GR) may result in repression of the expression of proinflammatory genes. HDAC forms a bridge with HAT to inhibit gene transcription. However, when the HDAC is inhibited by oxidants or the NF-κ B subunit p65 is acetylated, steroids may not be able to recruit HDACs into the transcriptional complex to inhibit proinflammatory gene expression.