Oxidative stress and antioxidant defense mechanisms linked to exercise during cardiopulmonary and metabolic disorders

Chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD) is a progressive, irreversible disease of the respiratory tract, characterized by limited or obstructed airflow, believed to be brought on by an abnormal and/or excessive inflammatory response in the lungs.33 Cigarette smoking is suggested to be the primary etiological factor in the development of COPD, as more than 90% of patients with COPD are smokers.34 Both inflammation and oxidative stress appear to play a critical role in the development and/or the progression of COPD (reviewed in ref. 33). Mechanistically, both RONS, as well as inflammatory cells likely exert both an independent, as well as an intricately connected impact on disease development, as both activate each other in a cyclical manner. This process has been reviewed recently,33,35,36 and it has been suggested that intra and extracellular RONS production via mitochondrial respiration and/or membrane bound NADPH or xanthine oxidase gives rise to the increased gene transcription of certain inflammatory cytokines, as well as the increased circulation of phagocytic cells.37 This increase in inflammation and circulating phagocytes (particularly macrophages and neutrophils) gives rise to further RONS production via activation of certain radical generating enzymes and/or phagocytic respiratory burst, respectively.33 Potential sources of increased RONS production and inflammation include exposure to cigarette smoke, other pollutants, ischemia/reperfusion injury to peripheral tissues resulting from inadequate lung function, as well as increased mitochondrial superoxide production.33 Because the latter two events can be brought about during an acute exercise session, several studies have investigated the impact of acute exercise on the systemic oxidative stress response in COPD patients. These studies are discussed below and presented in Table 1.

The impact of acute exercise on oxidative stress in COPD patients was first investigated by Vina and colleagues,38 who reported an increase in oxidized glutathione (GSSG) following cycle ergometry at an intensity comparable to normal activities of daily living (∼3 METS). This post-exercise increase in GSSG was prevented following supplemental administration of oxygen at a flow rate of 2–3 L•min⁻¹, suggesting a role of alternate RONS generating pathways (e.g., NADPH oxidase, xanthine oxidase) other than increased mitochondrial superoxide production, in eliciting an oxidative insult post exercise.38 In agreement with these findings, a similar study reported an increase in GSSG and malondialdehyde (MDA), as well as a decrease in reduced glutathione (GSH), following a graded exercise test (GXT) in COPD patients, which was prevented by infusion with 300 mg allopurinol 24 and one hour pre exercise.39 Allopurinol is a known inhibitor of the radical generating enzyme xanthine oxidase,40 which has been shown to be activated in response to periods of ischemia followed by reperfusion. Taken together, these results suggest that the impaired pulmonary function seen in COPD patients likely leads to an imbalance between oxygen supply and demand to the exercising musculature during acute exercise, potentially resulting in the increased production of RONS via xanthine oxidase. This increase in RONS appears evident even at low intensities comparable to activities of daily living, suggesting that patients with COPD may be under a chronic state of oxidative stress.38

Increased oxidative stress has also been reported in COPD patients following both acute maximal7,8,10,41 and submaximal7,10 aerobic exercise. This has been the case with one exception,42 evident by reported increases in MDA,8,10 thiobarbituric acid-reactive substances (TBARS),7,41 protein oxidation (protein carbonyls),41 DNA damage (comet assay),10 phagocytic superoxide production,7,41 as well as changes in glutathione redox status7 and other components of the antioxidant defense system (e.g., total antioxidant status).7 In those studies in which a healthy control group was utilized for comparison, exacerbated increases have been reported in COPD patients.7,8,10 These effects appear most pronounced in muscle-wasted COPD patients [fat-free mass <16 kg•m⁻² (men) or <15 kg•m⁻² (women)], as they have been shown to present with lower levels of GSH at rest, as well as experience greater increases in oxidative stress post exercise, compared to their non-muscle wasted counterparts.7 Hence, lower antioxidant defense may be a contributing factor to increased exercise-induced oxidative stress in those with COPD.

Although the majority of investigations using COPD patients have reported an increase in oxidative stress in response to exercise, significance has not been observed for all biomarkers studied (i.e., lipid, protein, DNA, antioxidant status). This is a common occurrence throughout the literature, as null findings for certain biomarkers may be related to the time to oxidation and “repair” of a given molecule. In this regard, inadequate sampling time may help to explain much of the variability in results,43 as the majority of studies have only taken samples immediately pre and post exercise.7,42,44,45

Aside from aerobic exercise, investigators have also measured the oxidative stress response in COPD patients following knee extension exercise performed at 30–40% maximal voluntary contraction until exhaustion.9,22,23,46 Findings have included increased lipid peroxidation,9,22,23,46 protein oxidation,9,23,46 and phagocytic superoxide production.9,46 Similar to aerobic exercise, exacerbated increases in oxidative stress biomarkers have been reported for COPD patients compared to healthy controls.9,23

Cleary, acute exercise has the ability to result in increased RONS and subsequent oxidative damage in COPD patients. Inadequate oxygen likely leads to an acute state of ischemia followed by reperfusion, resulting in the formation of RONS via radical generating enzymes (e.g., NADPH oxidase, xanthine oxidase). While two studies have successfully used antioxidants in patients with COPD to minimize the oxidative stress associated with acute exercise,8,46 exercise training has also been investigated and will be discussed in a later section.

Cardiovascular disease (CVD).

Cardiovascular disease (CVD) is the leading cause of death in the United States.47 Two common conditions that exist under the umbrella of CVD that contribute significantly to morbidity and mortality include congestive heart failure (CHF)17 and coronary artery disease (CAD).48 Oxidative stress has been suggested to play a role in either the primary or secondary etiology of both CHF17 and CAD,48 evident by increased oxidative stress biomarkers and/or decreased antioxidant defenses at rest in diseased compared to healthy controls.17 As with COPD, several mechanistic links related to increased RONS production in CVD have been identified, including increased NADPH and xanthine oxidase activity, increased mitochondrial superoxide production resulting from mitochondrial dysfunction, as well as enhanced circulating concentrations of inflammatory cytokines.49 Increased RONS production leads to an exacerbation of disease severity, illustrated primarily by the role of RONS in promoting endothelial dysfunction19 and atherogenesis,16 as well as cardiomyocyte apoptosis, left ventricular remodeling and depressed myocardial contractility.49 Exposure to excess RONS may lead to the increased accumulation of oxidized LDL (oxLDL) particles within the intima of arteries, thereby promoting atherogenesis and systemic inflammation.16 This increase in fatty lesion formation and a pro-inflammatory environment could lead to the development and/or progression of arterial disease, myocardial infarction or stroke.16 Myocardial infarction could in turn promote the development of CHF due to impaired ventricular performance, resulting in severely compromised functional capacity.

Exercise induced oxidative stress has been studied within patients with various forms of CVD, as presented in Table 2. Increased oxidative stress in response to a GXT has been noted in patients with both CHF12,25,26 and CAD,27,50 evident by increased MDA,12,25,50 oxLDL26 and expired breath pentane/ethane50, as well as decreased GSH27 and antioxidant enzyme activity.27 Moreover, in those studies in which a healthy control group has been utilized for comparison, exacerbated oxidative stress has been evident in those with CVD.12,25–27 In opposition to the above, null findings for lipid peroxidation have also been reported following a GXT in CAD patients.27,51 However, lipid peroxidation was assessed via TBARS, which has been shown to lack sensitivity.52

Similar to the above results for those with CHF or CAD, increased oxidative stress has been reported in subjects without diagnosed CAD but who presented with exercise-induced ischemia,53 as well as in subjects with peripheral vascular disease.28 It should be noted that infusion of vitamin C (50 mg/min) for 20 minutes pre exercise eliminated the post-exercise increase in TBARS,28 indicating a benefit of antioxidant treatment. In hypercholesterolemic subjects, a post-exercise increase in MDA has been reported following a GXT,54 a finding that may be partly explained by the increased superoxide production known to be present in hypercholesterolemic patients.55 Finally, no increase in MDA has been reported in heart transplant recipients following a GXT.56 However, the null findings may be due to the training status of the subject population, as all were aerobically trained and may have had improved antioxidant defense.56

Diabetes.

Diabetes is a condition characterized by chronic elevations in blood glucose brought on either via the autoimmune destruction of pancreatic beta cells (type 1) or the development of insulin resistance in the peripheral tissues (type 2).57 Both forms of diabetes are associated with an increased risk for developing microvascular (retinopathy, neuropathy) and macrovascular (atherosclerosis) complications, which have been linked to oxidative stress.57 Increased oxidative stress biomarkers have been reported in diabetics compared to healthy controls, and the role of RONS in diabetes etiology has been the topic of numerous reviews.18,58 It appears that this chronic exposure to hyperglycemic conditions gives rise to increased superoxide production resulting from postprandial hyperglycemia,18 glucose autooxidation,59 the formation of advanced glycation end products60 and activation of the polyol pathway.61

As with COPD and CVD patients, diabetics (in particular type 1) have been the focus of exercise-induced oxidative stress research (Table 3). Increased TBARS13,14 and GSSG13 have been reported following submaximal aerobic exercise in type 1 diabetic subjects. In regards to maximal exercise, direct production of RONS via electron spin resonance spectroscopy has been reported following a GXT; however, it is important to note that significance was only achieved when data for both type 1 diabetic and healthy control subjects were pooled.15 Despite the observation of increased levels of exercise-induced oxidative stress biomarkers in studies involving type 1 diabetics, when compared to healthy individuals, the relative magnitude of increase does not differ; rather the group differences at rest are merely maintained during the post exercise period. Other investigators have reported no changes in MDA,15 total glutathione (TGSH), antioxidant enzyme activity,14 or circulating antioxidants15 in response to acute exercise in type 1 diabetics.

Only one study to our knowledge has been conducted addressing the impact of acute exercise (GXT) on measures of oxidative stress (TBARS, GSH) in type 2 diabetics.62 Unfortunately, findings proved difficult to interpret, as the authors failed to report if the post exercise values were statistically significant from the pre exercise values; thus these are presented as null findings in Table 3. Taken together, unlike findings for patients with COPD and CVD, diabetic subjects do not appear to experience any further increase in exercise-induced oxidative stress compared to healthy controls.

Obesity.

Closely linked to the development of type 2 diabetes, obesity has been studied in relation to exercise and oxidative stress (Table 4). This association between these two disorders appears due to the increased circulating levels of tumor necrosis factor-α within obese individuals, which has been shown to be released from adipocytes63 as well as impart an insulin resistant state.64

Increased lipid peroxidation has been reported in obese individuals following acute submaximal29,31,65 and maximal30,66 aerobic exercise, as well as following a single session of resistance exercise.29 Moreover, obese individuals (BMI > 30 kg•m⁻²) have been noted to experience a greater magnitude of increase in selected biomarkers when compared to normal weight controls.29,30 However, these results appear mixed in overweight (BMI > 25 kg•m⁻²) populations, with studies reporting conflicting results.31,66

Cigarette smoking.

Although not a disease itself, cigarette smoking has consistently been shown to increase the susceptibility for the development of several disease conditions, including COPD,34 CVD67 and diabetes.68 Much of the detrimental effects of cigarette smoking have been attributed to their role in inducing a state of oxidative stress,69 as a single puff of a cigarette exposes an individual to more than 1015 free radicals in the gas phase alone, coupled with additional exposure in the tar phase equal to 1017 free radicals per gram.3 Elevated resting levels of oxidative stress biomarkers have been reported in smokers compared to nonsmokers.67,70–72 In regards to acute exercise-induced oxidative stress, three studies have been conducted to date (Table 5).

Maximal exercise in the form of a GXT has been shown to elicit an increase in lipid peroxidation (MDA,11 conjugated dienes24) and protein carbonyls11 in smokers despite no change in 8-hydroxydeoxyguanosine,11 lipid hydroperoxides or circulating antioxidants.24 Two studies noted an exacerbated increase in lipid peroxidation in smokers compared to nonsmokers.11,24 In opposition to the above results, one study noted no change in MDA, glutathione peroxidase (GPx) or superoxide dismutase (SOD), despite a decrease in vitamin E in smokers following 20 maximal knee extensions.73 However, it is possible that the exercise stress was insufficient to induce any significant increase in RONS.73