Is intrinsic aerobic exercise capacity a determinant of COPD susceptibility?

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Abstract

Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality, which is most commonly associated with smoking or exposure to environmental pollutants. Unfortunately, there is an inadequate understanding of the molecular and physiological determinants governing one's susceptibility for developing COPD. Here, we describe a novel hypothesis: Individuals with intrinsically low aerobic exercise capacity are more likely to develop COPD after exposure to key risk factors. The hypothesis is based on observations that aerobic exercise capacity is tightly associated with mortality across many complex diseases. The premise is supported by recent studies demonstrating that smokers who exercise regularly are less likely to develop or be hospitalized for COPD. Herein, we describe the evolutionary and molecular basis for this hypothesis and how it is a natural extension of previous theories explaining 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)

  • J. Myers et al.

    Exercise capacity and mortality among men referred for exercise testing

    N Engl J Med

    (2002)
  • U. Wisloff et al.

    Cardiovascular risk factors emerge after artificial selection for low aerobic capacity

    Science

    (2005)
  • J.C. Eisenmann et al.

    Aerobic fitness, body mass index, and CVD risk factors among adolescents: the Quebec family study

    Int J Obes (Lond)

    (2005)
  • T. Church

    The low-fitness phenotype as a risk factor: more than just being sedentary?

    Obes (Silver Spring)

    (2009)
  • F.B. Ortega et al.

    Cardiorespiratory fitness, adiposity, and incident asthma in adults

    J Allergy Clin Immunol

    (2010)
  • J. Garcia-Aymerich et al.

    Regular physical activity reduces hospital admission and mortality in chronic obstructive pulmonary disease: a population based cohort study

    Thorax

    (2006)
  • J. Garcia-Aymerich et al.

    Regular physical activity modifies smoking-related lung function decline and reduces risk of chronic obstructive pulmonary disease: a population-based cohort study

    Am J Respir Crit Care Med

    (2007)
  • A.C. Toledo et al.

    Aerobic exercise attenuates pulmonary injury induced by exposure to cigarette smoke

    Eur Respir J

    (2012)
  • R.P. Vieira et al.

    Anti-inflammatory effects of aerobic exercise in mice exposed to air pollution

    Med Sci Sports Exerc

    (2012 Jan 31)
  • D.S. Ramos et al.

    Low-intensity swimming training partially inhibits lipopolysaccharide-induced acute lung injury

    Med Sci Sports Exerc

    (2010)
  • C. Flo et al.

    Effects of exercise training on papain-induced pulmonary emphysema in Wistar rats

    J Appl Physiol

    (2006)
  • K.L. Timmerman et al.

    Exercise training-induced lowering of inflammatory (CD14+CD16+) monocytes: a role in the anti-inflammatory influence of exercise?

    J Leukoc Biol

    (2008)
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