Current Perspectives of Oxidative Stress and its Measurement in Chronic Obstructive Pulmonary Disease

Figures & data

Figure 1.  Schematic representation of oxidative stress. (a) In a healthy individual, there is an abundant of antioxidant capacities in the lungs to counteract inhaled oxidants from air pollution or acute exposures to cigarette smoke. (b) However, chronic smokers experience a reduced antioxidants and increased oxidant burden delivered from the cigarettes. At an early stage, the oxidant burden is still compensated by the antioxidant capacity but eventually (c) the oxidant burden overwhelms the body's antioxidant protection mechanism, leading to oxidative stress and the development of COPD.

Table 1.  Endogenous and exogenous sources of oxidants

Endogenous oxidant sources	Oxidants	Location
Electron transport system	O2. (oxygen radicals)	Airway epithelial cells
Xanthine oxidase	O2^−	Airway epithelial cells
	H2O2
Inflammatory Process:
1. Oxidative bursts:	Free Oxygen Radicals	Phagocytes:
- Myeloperoxidase enzyme	Superoxides	Monocytes
- Eosinophil peroxidise	Nitric Oxides	Neutrophils
- Heme peroxidase		Eosinophils
2. NADPH oxidases
3. Nitric oxide synthase
Exogenous oxidant sources	Oxidants	Location/mechanism
Cigarette smoking	Superoxides	Induce lung injury and local inflammation in the airways/lungs
H2O2
Peroxy-nitrate
Peroxy-nitrite
Air pollution	SO2, NO2, O3	Polluted air
Infection	Mainly ROS	By inducing lung injury and inflammation.

Figure 2.  Consequences of airway damage by oxidative stress. Oxidative stress causes airway damages at three levels: airway changes, cellular changes, and biochemical changes. These factors contribute to lung injury and inflammation, which leads to the development of COPD. The ongoing oxidant injuries and inflammation in COPD feeds back to the increased airway damage, restarting the vicious cycle.

Figure 3.  Vicious cycle of oxidative stress and inflammation (adapted from Lee 2009) (154). Oxidative stress generated by cigarette smoking increases ROS production in the bronchial mucosa, leading to the recruitment of inflammatory cells, which further increases oxidative stress. These phenomena cause lung injuries, which further enhances lung tissue inflammation and the generation of more ROS.

Table 2.  Mechanisms of controlled apoptosis (Recreated from Demedts 2006; Hodge 2005) (30, 35)

	Mechanisms
Extra-cellular apoptotic pathways
Receptor-mediated extrinsic pathway	Mediators of the TNF family can bind to cellular surface “death” receptors resulting in the proliferation of death receptors as well as an activation of caspase pathways.
Cytolytic pathway	Cytotoxic T-cell can release enzymes such as granzyme B and perforin to induce cellular apoptosis.
Growth factor inhibition	Depletion of cellular growth factors leads to apoptosis by the activation of cytochrome C (see below).
Intra-cellular apoptotic pathways
Mitochondrial pathway	In response to stress, mitochondria releases cytochrome C (Cyt C). Together with apoptotic-protease-activating-factor and pro-caspase, Cyt C signals proteolytic activation and cell death.
Endoplasmic reticulum pathway	As a reaction to stress such as hypoxia, the endoplasmic reticulum can directly induce cell death via activating caspase-12, or indirectly induce apoptosis by stimulating the mitochondrial pathway.

Table 3.  Summary of genetic association studies of COPD with EcSOD (Reproduced from Oberley-Deegan et al. 2009) (78)

Reference	Study population	Subjects	Findings
Juul et al. (2006) (91)	Danish Population	n = 9258	EcSOD R213G mutation protects smokers from COPD.
Young et al. (2006) (90)	European Decent Population	n = 440
Wilk et al. (2007) (89)	Framingham Heart Study	n = 1758	SNPs near EcSOD gene exhibited association with lung function.
Dahl et al. (2008) (155)	Copenhagen City Heart Study	n = 9093	An EcSOD polymorphism (E1/l1) was associated with COPD morbidity.
	Copenhagen General Population Study	n = 35,635	No association of EcSOD (E1/l1) with COPD morbidity was found.
Arcaroli et al (2009) (156)	In vitro study of EcSOD genetic variant	In vitro study	EcSOD haplotypes are associated with acute lung injury and mortality.

Figure 4.  Diagrammatic representation of the GSH redox system. The oxidant hydrogen peroxide (H₂O₂) generated from oxidative stress is neutralized by the glutathione redox system with the assistance of GSH-reductase and glutathione peroxidase.

Figure 5.  Integrated diagram of oxidative stress and the heme breakdown pathway by HO-1. Heme is a product of haemoglobin metabolism and is further broken down into carbon monoxide, iron, and biliverdin, which is then converted into bilirubin. Each of these downstream products of heme metabolism has antioxidant capacities that function at different levels. CO acts as anti-inflammatory, anti-apoptotic, anti-proliferative agent. The iron-storage protein ferritin has antioxidant actions that counteract oxidative stress, and bilirubin is also an antioxidant and anti-inflammatory molecule.

Table 4.  Recent clinical trials for the efficacy of antioxidants in pulmonary disease and in the general population

References	Antioxidant used	Disease condition	Aim of the study	Result/outcome
Stav D (2009) (112)	NAC	COPD	Effect of NAC on FVC and exercise tolerance.	NAC has beneficial effect on physical performance in 24 patients.
Sagiura et al. (2009) (157)	NAC	COPD	Effect of NAC on TGF-β1 mediated tissue remodelling/production of VEGF, fibronectin.	NAC significantly decreased TGF-β1 augmented fibronectin and VEGF production in vitro.
Schermer et al. (2009) (116)	NAC	COPD/chronic bronchitis	Effect of NAC in primary care patients.	No beneficial treatment were observed in the study population (n = 286).
Zuin et al. (2005) (137)	NAC	COPD exacerbation	Effect of high dose NAC (1200mg/day) in treatment of COPD exacerbation.	Improved biological markers and clinical outcomes in exacerbated COPD.
Decramer et al. (2001, 2005) (158, 117)	NAC	COPD	Effect of NAC on FEV1.	30% reduction in COPD hospitalization obtained without change on decline in FEV1.
Kirkil et al. (2008) (159)	Zinc picolinate	COPD	Effect of zinc supplementation on oxidant stress and pulmonary function test (PFT).	May have a favorable effect on oxidant–antioxidant balance. PFT showed no significant improvement probably due to the short duration of supplementation.
Hirayama et al. (2009) (135)	Diet high in vegetables and fruits	COPD	Investigate relationship between vegetable and fruit consumption and risk of COPD.	Inverse association between vegetable consumption and risk of COPD.
Nadeem et al. (2009) (160)	Vitamin E	COPD	Effect of Vitamin E supplementation on oxidative stress.	No significant benefits.
Conklin et al. (2010) (161)	Vitamins C and E, alpha-lipoic acid	COPD	Effect of antioxidants on skeletal muscle oxygen delivery and blood flow.	Oxidative stress determines skeletal muscle blood flow and muscle metabolism in COPD.
Wu et al. (2007) (110)	Vitamins C and E	COPD	Effect of vitamins C and E on white blood cell DNA damage.	Vitamin E or C may improve resistance of DNA in WBC against oxidative challenge.
Guenegou et al. (2006) (109)	Vitamin E β-carotene	Lung function	Effect of low level serum β-carotene and vitamins A and E on 8-year lung function.	β-carotene protects against decline in FEV1. Both β-carotene and vitamin E are protective of lung function decline in heavy smokers.
Griese et al. (2004) (139)	Inhaled GSH	Cystic fibrosis	Effect of GSH on lung function and oxidative stress.	Improvement in lung function but no change in oxidative stress state of the lungs.
Bishop et al. (2005) (140)	Inhaled GSH	Cystic Fibrosis	Effect of GSH on clinical parameter of CF patients.	Improvement in clinical parameters.