Oxidative Stress in COPD: Sources, Markers, and Potential Mechanisms

Abstract

Markers of oxidative stress are increased in chronic obstructive pulmonary disease (COPD) and reactive oxygen species (ROS) are able to alter biological molecules, signaling pathways and antioxidant molecule function, many of which have been implicated in the pathogenesis of COPD. However, the involvement of ROS in the development and progression of COPD is not proven. Here, we discuss the sources of ROS, and the defences that have evolved to protect against their harmful effects. We address the role that ROS may have in the development and progression of COPD, as well as current therapeutic attempts at limiting the damage they cause. Evidence has indicated that the function of several key cells appears altered in COPD patients, and expression levels of important oxidant and antioxidant molecules may be abnormal. Therapeutic trials attempting to restore equilibrium to these molecules have not impacted upon all facets of disease and whilst the theory behind ROS influence in COPD appears sound, current models testing relevant pathways to tissue damage are limited. The heterogeneity seen in COPD patients presents a challenge to our understanding, and further research is essential to identify potential targets and stratified COPD patient populations where ROS therapies may be maximally efficacious.

Keywords: COPD; antioxidant; antiproteinase; macrophage; mechanisms; neutrophil; oxidative stress; therapeutic studies.

Figure 1

Molecular production of reactive species. Initiated by an inflammatory stimulus, a cascade begins that results in a variety of oxidative agents. Red boxes represent pro-inflammatory enzymes, whilst blue boxes represent anti-inflammatory enzymes. Superoxide dismutase (SOD) may be classed as both as its substrate and product are both capable of causing harm. NOX2, nicotinamide adenine dinucleotide phosphate(NADPH)-oxidase; iNOS, inducible nitric oxide synthase; O₂·⁻, superoxide anion; ·NO, nitric oxide; SOD, superoxide dismutase; H₂O₂, hydrogen peroxide; CAT, catalase; GPx, glutathione peroxidase; MPO, myeloperoxidase; HOCl, hypochlorous acid; RCS + RNS, reactive nitrogen species + reactive carbon species; ONOO¯, peroxynitrite.

Figure 2

Process of tissue damage in chronic obstructive pulmonary disease (COPD). 1. Influx of pro-inflammatory particles into lung. 2. Particles bind PRRs on the surface of lung epithelial or tissue macrophages, instigating a signalling cascade culminating in the release of pro-inflammatory cytokines. 3. Cytokines encourage the recruitment, migration and activation of peripheral neutrophils and monocytes, the latter of which mature to alveolar macrophages once recruited. Activation of these cells results in the further cytokine release, proteases and ROS, in turn fueling further recruitment and activation. In health, anti-proteases and anti-oxidants are present in very high levels, preventing excess damage to surrounding tissues, and limiting a positive feedback loop. In COPD, these levels may be lacking, resulting in increased areas of obligate tissue damage. 4. If insufficiently inhibited, proteases will degrade extracellular matrix, leading to tissue destruction and pathologies seen in COPD. O₂·¯, superoxide anion; ·NO, nitric oxide; SOD, superoxide dismutase; H₂O₂, hydrogen peroxide; CAT, catalase; GPx, glutathione peroxidase; MPO, myeloperoxidase; HOCl, hypochlorous acid; ONOO⁻, peroxynitrite; TNFα, tumour necrosis factor α; IL8, Interleukin 8; MCP-1, monocyte chemoattractant protein 1; LPS, lipopolysaccharide; PRR, pattern recognition receptor; GSH, glutathione; PR3, proteinase 3; NE, neutrophil elastase; MMP9, matrix metalloproteinase 9; α1AT, α1 antitrypsin; SLPI, secretory leukocyte protease inhibitor.