Oxidative Stress in Chronic Obstructive Pulmonary Disease

Abstract

There is a marked increase in oxidative stress in the lungs of patients with COPD, as measured by increased exhaled 8-isoprostane, ethane, and hydrogen peroxide in the breath. The lung may be exposed to exogenous oxidative stress from cigarette smoking and indoor or outdoor air pollution and to endogenous oxidative stress from reactive oxygen species released from activated inflammatory cells, particularly neutrophils and macrophages, in the lungs. Oxidative stress in COPD may be amplified by a reduction in endogenous antioxidants and poor intake of dietary antioxidants. Oxidative stress is a major driving mechanism of COPD through the induction of chronic inflammation, induction of cellular senescence and impaired autophagy, reduced DNA repair, increased autoimmunity, increased mucus secretion, and impaired anti-inflammatory response to corticosteroids. Oxidative stress, therefore, drives the pathology of COPD and may increase disease progression, amplify exacerbations, and increase comorbidities through systemic oxidative stress. This suggests that antioxidants may be effective as disease-modifying treatments. Unfortunately, thiol-based antioxidants, such as N-acetylcysteine, have been poorly effective, as they are inactivated by oxidative stress in the lungs, so there is a search for more effective and safer antioxidants. New antioxidants in development include mitochondria-targeted antioxidants, NOX inhibitors, and activators of the transcription factor Nrf2, which regulates several antioxidant genes.

Keywords: 8-isoprostane; Nrf2; antioxidants; cellular senescence; inflammation.

Figure 1

Increased exogenous and endogenous oxidative stress in COPD, which is enhanced by reduced endogenous and dietary antioxidants. ↑: increased; ↓: decreased.

Figure 2

Increased markers of oxidative stress in the breath of COPD patients. Left panel shows increased concentrations of 8-isoprostane in exhaled breath condensate from normal smokers and a greater increase in COPD patients. Ex-smokers have a similar level of 8-isoprostane to active smokers, indicating endogenous oxidative stress from chronic inflammation in the lungs (adapted from ref. [37]). Right panel shows increased exhaled ethane (measured by gas-chromatography mass spectrometry) in COPD patients compared with smokers (adapted from reference [33]). Difference from normal controls: * p < 0.05, ** p < 0.01, *** p < 0.001.

Figure 3

Increased oxidative stress drives the pathology of COPD through several mechanisms. These include the proinflammatory transcription factor nuclear factor-KB (NF-κB), p38 mitogen-activated protein kinase (MAPK), generation of autoantibodies to carbonylated proteins, reduced expression of sirtuin-1 (resulting in cellular senescence), DNA damage (increasing lung cancer risk), reduced histone deacetylase (HDAC)-2 expression (inducing steroid resistance), reduced activity of antiproteases (resulting in emphysema), increased release of transforming growth factor(TGF)-β (resulting in small airway fibrosis), and increased expression of mucin genes (MUC) (causing mucus hypersecretion. ↑: increased; ↓: decreased; ┴: block.