Associate editor: A. TrifilieffAerobic capacity, oxidant stress, and chronic obstructive pulmonary disease—A new take on an old hypothesis
Introduction
Chronic obstructive pulmonary disease (COPD) is a collective group of lung conditions that result in a significant loss of lung function. It is the fourth most common cause of chronic morbidity and mortality in the United States. As many as 120,000 Americans died from this disease in 2002. Approximately 80–90% of COPD deaths are coupled with a history of smoking. In 2002, another 11.2 million Americans were diagnosed with the disease while 24 million others had evidence of impaired lung function, indicating that this disease is underdiagnosed. The costs for COPD to the United States last year were approximated at $37.2 billion. In the year 2020, COPD is projected to be the third leading cause of death worldwide (American Lung Association, 2005).
COPD is defined by the Global Initiative on Obstructive Lung Disease criteria as “airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases” (Pauwels et al., 2001). The pathological changes that contribute to the loss in lung function are heterogeneous in nature consisting of parenchymal destruction (described clinically as emphysema), remodeling and thickening of the airways (described clinically as small airways disease), and mucus hypersecretion (described clinically as chronic bronchitis). These changes occur at every level of the airways. In the central airways, the main pathological changes are enlargement of the mucus glands, goblet cell metaplasia, epithelial thickening (hypertrophy and hyperplasia), ciliary dysfunction, smooth muscle hypertrophy, and subepithelial inflammation (neutrophils, macrophages, and CD8+ T-cells). The peripheral airways have many of these same features as well as subepithelial fibrosis/matrix deposition that contribute to the fixed airway obstruction associated with the disease. In the parenchyma, destruction of the respiratory bronchioles (centrilobular emphysema), alveolar walls, and capillary beds affect lung mechanics and gas exchange capabilities (Pauwels et al., 2001, Hogg, 2004). These morphological changes occur as focal lesions in the tissue and may vary in degree between affected patients (Hogg, 2004). There are also systemic consequences associated with smoking that are observed in COPD patients. The most notable involves significant skeletal muscle alterations affecting both the mobility of patients and their ability to respire properly (Wouters et al., 2002, Barreiro et al., 2005).
Cigarette smoke is a major source of particles, free radicals, and reactive chemicals and gases, all of which can produce an overwhelming oxidant burden on the lungs that are thought to play a central role in the pathogenesis of COPD. The molecular effect of these highly reactive molecules can explain a number of the pathologies observed in COPD patients—namely, inflammation, emphysema, airway fibrosis, mucus hypersecretion, and skeletal muscle wasting. However, only 15–50% of smokers are diagnosed with COPD; therefore, there must be genetic and/or environmental factors that play a role in determining susceptibility (Lundback et al., 2003). Because oxidant stress is believed by many to be central to the disease process, it has been suggested that differences in individual antioxidant defenses may hold the key to understanding COPD susceptibility, but no studies have demonstrated a clear link or plausible mechanism for this deficiency. We propose that smokers' aerobic capacity—that is, a complex, polygenetic trait closely associated with mitochondrial function and antioxidant capacity—may determine whether they are susceptible to developing COPD.
Section snippets
Hypothesis
Complex diseases, like COPD, result from a diversity of genetic, developmental, and environmental factors. The vast majority of COPD patients (80–90%) share chronic cigarette smoke exposure as a common (and primary) environmental etiological factor. The individual genetic profiles of these patients are likely to be very different, comprised of multiple allelic variations across a number of different genes. However, we propose that their genetic profiles also share at least one common phenotypic
Smoking and oxidant stress
Smoking is the main etiological factor in the development of COPD (U.S. Department of Health and Human Services, 2004). Cigarette smoke contains the equivalent of 1017 radicals per gram in the tar phase of smoke (the approximate daily intake of a pack-a-day smoker) and 1015 radicals per puff in the gas phase (Church & Pryor, 1985). Reactive oxygen species (ROS), reactive nitrogen species (RNS), and carbon-centered radicals are constituents in both the tar and gas phases of smoke and more can be
Oxidant stress and chronic obstructive pulmonary disease
The proposal of the oxidant/antioxidant imbalance hypothesis for COPD is based on evidence for an increased level of oxidant damage, both locally and systemically, in COPD patients compared to healthy smokers (Taylor et al., 1986, Rahman & MacNee, 1996, Repine et al., 1997). Montuschi et al. (2000) measured 8-isoprostane, a marker of free radical-induced lipid peroxidation of arachidonic acid, in the exhaled breath of the following: (1) healthy subjects, (2) healthy smokers, (3) COPD patients
Antioxidant capacity and chronic obstructive pulmonary disease
It is clear that the molecular effects of ROS and RNS can lead to a number of the pathological and physiological changes that comprise COPD (Fig. 3). In addition, clinical studies have demonstrated that oxidant damage is greater in COPD patients compared to healthy smokers. However, questions remain with respect to the role that antioxidant capacity plays in the disease process. First, is antioxidant capacity important for protection from these cigarette smoke-induced pathologies? And second,
The effects of smoking on mitochondrial function
The observation that COPD patients have less of a change in redox potential in response to exercise training has interesting implications for mitochondrial function, which is related to both O2 consumption, and ROS generation during exercise (Rabinovich et al., 2001). Inefficient mitochondrial function is known to lead to added oxidant stress levels; therefore, mitochondrial dysfunction may play a direct role in the development of COPD.
The etiology of chronic obstructive pulmonary disease
The critical question remains: Is mitochondrial dysfunction the underlying causative feature in COPD? Once believed to be uncommon, deficiencies in mitochondrial function are associated with a number of multi-system disorders including degenerative diseases like Alzheimer's disease, neuromuscular diseases, type II diabetes, cardiovascular disease, and some cancers (Houten & Auwerx, 2004). These disorders are adult-onset, their prevalence increases with age, and smoking has been implicated as an
Summary
The concept that aerobic capacity is a major determinant in the continuum between health and disease could explain the heterogeneity observed in many multifactorial diseases, like COPD. Cigarette smoke creates an environmental oxidant hazard for chronic smokers both in the lung and systemically. This can lead to a number of destructive changes, but only a percentage of smokers develop severe pathologies resulting in COPD. The concept that COPD patients have a reduced ability to adapt their
Acknowledgments
We are grateful to Dr. Yong Han, Dr. Henry Danahay, Dr. Alan Jackson, Dr. Alex Trifilieff, and Dr. John Fozard for their insights, suggestions, and careful review of this manuscript. In addition, we would like to thank Prof. Peter Barnes, Dr. William Pryor, Dr. Jonathan Myers, Prof. Yau-Wuei Wei, the New England Journal of Medicine, the American Journal of Respiratory and Critical Care Medicine, the New York Academy of Sciences, and the Society for Experimental Biology and Medicine for their
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