Is intrinsic aerobic exercise capacity a determinant of COPD susceptibility?
Introduction
Chronic obstructive pulmonary disease (COPD) is a syndrome characterized by airflow limitation that is progressive and largely irreversible. In the vast majority of patients, the airflow obstruction is due to structural changes to the distal airways, resulting from smoking heavily for many years. In the smaller airways, the injury leads to airway wall inflammation, subepithelial fibrosis, and inflammatory mucus exudates (aspirated down from the central airways) occluding the lumen of the bronchioles [1]. Further, destruction of the alveoli (i.e. emphysema) also leads to an increased incidence of dynamic small airways collapse because the alveolar walls provide structural support to the airways to maintain small airway patency. How smoking induces these changes is not entirely clear. Dogma suggests that the free radicals in the smoke and those generated by inflammatory cells injure the lung tissue and cause these pathologies; however, direct clinical evidence to substantiate these theories are still lacking.
As with other complex diseases, it is important to note that not all individuals exposed to risk factors associated with COPD (i.e. cigarette smoke) develop the disease. In fact, only about 25% of the smoking population are said to be susceptible [2]. The mechanisms underlying COPD susceptibility have been poorly defined and non-specific, generally attributed to a gene-by-environment interaction. Unfortunately, little clarity has been born out of the genome-wide association studies that have now been completed in several COPD patient cohorts [3]. Many of the single nucleotide polymorphisms (SNPs) that have been identified in these studies occur in genes associated with inflammation or the response to free radical stress; nevertheless, these associative studies have not, as yet, made any impact on treatment paradigms for these patients.
Studies approaching the problem from the preclinical side have fared no better. For over 20 years, several groups have now used animal models of smoking-induced lung injury to assess the efficacy of candidate mechanisms. To date, no therapy that has shown efficacy in these models has yet made a substantial impact on the therapeutic options available to patients. The failure to identify new treatments may be due, in part, to the departure from using classical, integrative physiological approaches to interrogate disease mechanisms. Instead, the primary tactic for investigating disease mechanisms has been to grossly overexpress or completely delete the expression of specific molecular targets to implicate these single entities as causative factors instigating the onset of complex, heterogeneous diseases. While these techniques are valuable tools, we and others have argued that complex diseases are not likely to stem from the interaction between a mutation in a single gene and an environmental trigger; rather these diseases are the result of the combined expression of allelic variants in several genes whose functions are sensitive to a given environment [4], [5], [6]. As such, new paradigms are now warranted to identify therapies to impact diseases, such as COPD. Replacing the practice of molecular modification of single genes with approaches that concentrate on defining and modeling physiological traits that are commonly observed in disease-susceptible populations are required to determine whether these polygenic traits play a causative role in disease pathogenesis.
Section snippets
Exercise capacity, metabolism, and COPD–are they linked?
Aerobic exercise capacity is a complex trait that has been shown to be the most powerful predictor of mortality across several disease indications [7]. Whether the reduced exercise capacity is a cause or consequence of these conditions is still an open question; however, more recently several lines of evidence indicate that reduced aerobic fitness is a key risk factor associated with several diseases [8], [9], [10], [11].
Consistent with these observations, physical activity has been shown to
The aerobic hypothesis to explain COPD susceptibility
The “original” hypothesis to explain the pathogenesis of COPD was the proteinase-antiproteinase hypothesis. It argued that smokers who are susceptible for developing COPD have inadequate antiproteolytic defenses, which allowed proteinases secreted from inflammatory cells to damage the lung matrix and cause the emphysema associated with the disease. The hypothesis was based on two key observations; (1) Patients with an early-onset and familial form of emphysema had a genetic mutation which
Using a new animal model for complex diseases to test our hypothesis
Britton and Koch opted to take a new approach for developing an improved model of chronic disease in small laboratory animals. Namely, they chose to use artificial selection for a complex trait that was commonly associated with chronic diseases and predictive of mortality – i.e., aerobic exercise capacity [7]. Artificial selection was not a new approach as it has been used to create other disease models, such as the spontaneously hypertensive rat model. The new direction taken by Britton and
Conclusion
The aerobic hypothesis for COPD proposes that individuals with low aerobic capacity will be less capable of protecting against and repairing the (oxidant) damage elicited by smoking and therefore, would be at a greater risk of developing COPD. Several lines of evidence are now converging to support the aerobic hypothesis and strategies aimed at improving aerobic capacity, specifically regular exercise, appear to prevent the onset and delay the progression of COPD.
Acknowledgments
CSS's work on aerobic capacity in chronic pulmonary diseases is supported by a Wellcome Trust grant 088284/Z/09/Z. CSS was also supported by a project grant from the Medical Research Council, (MRC, UK, G0800196). CSS and LYB were supported by a Capacity Building Award in Integrative Mammalian Biology funded by the BBSRC, BPS, HEFCE, KTN, and MRC.
References (44)
Pathophysiology of airflow limitation in chronic obstructive pulmonary disease
Lancet
(2004)- et al.
Aerobic capacity, oxidant stress, and chronic obstructive pulmonary disease–a new take on an old hypothesis
Pharmacol Ther
(2006) - et al.
The effects of physical exercise on the cigarette smoke-induced pulmonary oxidative response
Pulm Pharmacol Ther
(2009) - et al.
Exercise training improves the antioxidant enzyme activity with no changes of telomere length
Mech Ageing Dev
(2008) - et al.
Moderate exercise is an antioxidant: upregulation of antioxidant genes by training
Free Radic Biol Med
(2008) - et al.
Inhibition of tobacco smoke-induced lung inflammation by a catalytic antioxidant
Free Radic Biol Med
(2002) - et al.
Developing COPD: a 25 year follow up study of the general population
Thorax
(2006) Progress in chronic obstructive pulmonary disease genetics
Proc Am Thorac Soc
(2006)- et al.
Animal models of complex diseases: an initial strategy
IUBMB Life
(2005) - et al.
PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes
Nat Genet
(2003)