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 proinflammatory 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.

Oxidative stress and free radicals in COPD – implications and relevance for treatment

“…The situation is drastic in smokers, since cigarette smoke, as the most important and preventable risk factor for COPD, contains about 5,000 different chemical compounds, as well as a high inhalative environmental burden of more than ten different oxidants and 15 FR. 27 , 28 This environmental oxidant burden is augmented by additional release of endogenous oxidants from a larger number of inflammatory airway cells with high capacity for FR production, especially in COPD patients who smoke. 8 Besides tobacco smoke with high contents of exogenous FR, urban (biomass fuel), industrial, and occupational air pollution provide various oxidants that probably are responsible for the high prevalence rates of COPD in nonsmokers in developing countries.…”

“…Even though supplementation seems to be the logical therapeutic consequence in COPD, administration of GSH, whether by the oral, intravenous, or inhalatory route, has not proven to effectively increase its concentrations in either respiratory cells or ELF. 28 , 73 Inhaled GSH produced some improvements in lung function, mainly in cystic fibrosis (CF) patients, but without any changes in the oxidative stress burden. 74 Novel, possibly liposomal formulations to improve its bioavailability could have promise for the future.…”

COPD and squamous cell lung cancer: aberrant inflammation and immunity is the common link

“…Activation of leukocytes by cigarette smoke generates superoxide radicals (O 2 ●− ), which can then either react with NO to form reactive peroxynitrite (ONOO − ) or alternatively be rapidly converted to hydrogen peroxide (H 2 O 2 ) under the influence of superoxide dismutase. Non‐enzymatic production of the more damaging hydroxyl radical ( ● OH) from H 2 O 2 through Fenton reactions catalysed by free iron can also proceed (Vlahos and Bozinovski, ). ROS activity as assessed by measuring exhaled H 2 O 2 in current smokers and patients with COPD is significantly higher than non‐smokers (Nowak et al ., ), and levels are further increased during exacerbations of COPD due to increased release of O 2 ●− (Dekhuijzen et al ., ).…”

Altered antioxidant enzyme activity with severity and comorbidities of chronic obstructive pulmonary disease (COPD) in South Indian population

“…Catalase (CAT) enzyme completes the detoxification process initiated by SOD via decomposition of H 2 O 2 to water and oxygen [13]. Glutathione peroxidase (GPx) is a family of seleniumdependent and independent antioxidant enzymes [14]. There are six known isoforms of GPx and the most abundant isoforms, GPx-1, is ubiquitously expressed in the cytoplasm of all mammalian cells [15,16].…”