Glutathione peroxidase-1 as a novel therapeutic target for COPD

Abstract

Oxidative stress plays a role in a variety of diseases but it is even more pertinent in chronic obstructive pulmonary disease (COPD) given the increased oxidant burden in smokers. The increased oxidant burden results from the fact that cigarette smoke contains over 4700 different chemical compounds and more than 10(15) oxidants/free radicals per puff. Other factors, such as air pollutants, infections, and occupational dusts that may exacerbate COPD, also have the potential to produce oxidative stress. These oxidants give rise to Reactive Oxygen Species (ROS) that are generated enzymatically by inflammatory and epithelial cells within the lung as part of an inflammatory immune response towards a pathogen or irritant. Thus, while ROS are necessary for host defence against invading pathogens, increased levels of ROS have been implicated in initiating inflammatory responses in the lungs through the activation of transcriptional factors, signal transduction pathways, chromatin remodelling and gene expression of pro-inflammatory mediators. However, the normal lung has developed defences to ROS-mediated damage, which include antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. In this review we consider the therapeutic potential of the antioxidant enzyme glutathione peroxidase-1 for the treatment of cigarette smoke-induced lung inflammation and damage.

Figure 1.

Sources and production of ROS in the lung. Activation of macrophages, neutrophils, and epithelium by cigarette smoke generates superoxide radicals (O₂^•−) which can then either react with nitric oxide (NO) to form reactive peroxynitrite molecules (ONOO⁻) or alternatively be rapidly converted to damaging hydrogen peroxide (H₂O₂) under the influence of SOD. This in turn can result in the non-enzymatic production of damaging hydroxyl radical (^•OH) from H₂O₂ in the presence of Fe²⁺. H₂O₂ is subsequently enzymatically reduced by glutathione peroxidases (Gpxs), including Gpx-1, as well as catalase (CAT). Gpx-1 uses GSH as a cofactor to reduce H₂O₂, resulting in the formation of oxidized glutathione (GSSG), which can then be reduced to GSH by glutathione reductase (GR). The ROS O₂^•−, ONOO⁻, H₂O₂, and ^•OH can then cause lung inflammation, DNA damage, protein denaturation, lipid peroxidation, and emphysema.