Asthma Risk: Possible Etiologies

Read Also

The etiology underlying the increased asthma risk among overweight children is unknown.  Several theories exist that have been detailed previously [20, 27, 28].  These include abnormal circulating inflammation and oxidant stress, obesity-related comorbidities, chest restriction with airway closure, and shared genetics.  One or more of these mechanisms may play a role in animal models of obesity and lung responses.  In murine models, obesity appears to: 1) increase innate airway responsiveness, 2) increase airway responses to common asthma triggers, and 3) increase airway inflammatory responses.  These same obesity-related responses have not been conclusively demonstrated in children.  Assessing lung inflammation and responses among obese children remains challenging and limited by current technologies.  Therefore, discussion about the link between obesity and asthma risk among children remains speculative.

One hypothesis for the obesity-asthma link is that obesity-related circulating inflammation primes the lung for exaggerated responses to environmental triggers, leading to asthma-like symptoms.  This notion is plausible since chronic inflammation and oxidative stress are hallmarks of both obesity and asthma.  Asthmatic and obesity-related inflammation involves similar mediators, including TNFα [29, 30]  and leukotrienes [31-33].  Adipose releases pro-inflammatory ‘adipokines’ that impact multiple organ systems, including the lung [29, 34].  These molecules (e.g. adiponectin, IL-6, TNFα, leptin) impact inflammation and can alter lung responses [34-37].  Therefore, obesity-related inflammation may play a role in the development and severity of asthma [38] that may be a distinct phenotype from the common atopic childhood phenotype.  Despite the excess in circulating markers of inflammation, obesity does not appear to be independently related to increased airway inflammation in children. 

Another hypothesis proposes that obesity-related co-morbidities may increase the risk for asthma diagnosis.  Gastro-esophageal reflux is increased among obese children and adults, and has been proposed as a trigger for cough and wheezing.  However, evidence in children remains lacking that gastric reflux alone triggers greater asthma diagnosis.  Obesity increases the risk for sleep-disordered breathing including obstructive sleep apnea.  It is rationale to hypothesize that altered sleep leading to episodic hypoxemia or other mechanisms may predispose to asthma. When controlling for both obesity-related esophageal reflux and obesity-related sleep apnea, the relationship between obesity and asthma among adults remains unchanged [39, 40].  These co-morbidities require further research in the pediatric age group.

In various models, obesity-related chest restriction has been shown to alter healthy airway physiology in two ways.  Compression of the lungs and chest wall reduces tethering of the airways by the surrounding lung parenchyma, leading to reduced airway caliber.  Obesity-related chest wall restriction also has been associated with reduced total lung capacity and a breathing pattern characterized by reduced functional residual capacity and tidal volumes.  Normal tidal breathing with periodic deep “sigh” breaths serves to stretch airway smooth muscle, detach actin-myosin cross-bridges and maintain normal cyclic bronchodilation and airway caliber.  Restricted respiration seen in the obese involves reduced airway dilation [41], likely due to unloading of airway smooth muscle and greater smooth muscle tone.  Over time these changes could lead to fixed reductions in airway caliber and enhanced airway responsiveness[42].  These physiologic characteristics seen in obese adults may be more subtle and variable in children [43-48] and may play a reduced role in obesity-related pediatric asthma symptoms.

Lifestyle factors related to obesity may also play a role in asthma risk.  The typical “Western” high-fat diet contains up to 25-fold more omega-6 (n-6) polyunsaturated fatty acids (PUFA) than n-3 PUFAs.  This 25:1 ratio is much higher than the 1-2:1 ratio typical for humans during the majority of evolution [49-51].  A “Mediterranean” diet higher in antioxidants from fruits and omega-3 fatty acids appears to protect from recurrent wheezing in young children[52].  A diet with elevated n-6 PUFA appears to increase production of inflammatory mediators from the 5-lipoxygenase pathway, and increases free radical generation and oxidative stress [53-56].   Also, increases in dietary and inflammatory cell n-3/n-6 fatty acid ratio have been associated with improvements in asthma outcomes [57-61].  Importantly, obese individuals have been shown to consume more n-6 dietary PUFAs, and have a reduced n-3/n-6 ratio in their diet compared to leans [62].  Obese adolescents do appear to have lower n-3 PUFA (especially DHA) and lower n-3/n-6 PUFA serum levels compared to lean adolesents [63].  The pattern of essential fatty acids among obese adolescents appears to differ significantly from leans, suggesting there may exist abnormal essential n-3 PUFA metabolism in the obese.  A typical high-fat ‘Western’ diet maintains a low leukocyte phosholipid membrane n-3/n-6 PUFA ratio, leading to greater cellular expression of 5-lipoxygenase pathway products, (such as leukotrienes), TNFα, and other molecules important in asthma pathogenesis [64-67]. 

A second lifestyle factor that is an important consideration in the obesity-asthma link is physical activity.  Children who are overweight or obese sustain less routine physical exertion than lean counterparts.  Some reports suggest that physical activity may be important in reducing asthma-risk [68] and reducing asthma symptoms [69-71], though other reports have not corroborated these findings [14, 52].  Lucas et al has raised the concern that past cohort studies have not adequately controlled for reduced physical activity, raising the question of whether reduced activity in combination with other obesity-related factors may be the cause of increased asthma incidence [21].  Within repeated exercise comes hyperventilation, cyclic ASM stretch, and bronchodilation.  In-vitro studies suggest that exercise-related cyclic respiratory epithelial compression may improve airway clearance and caliber[72]. 

It would also be rationale to hypothesize that the obesity-asthma link stems from common genetic origins [28, 73]. It is likely that genes contributing to one multi-factorial complex disease contribute directly or indirectly to other multi-factorial complex diseases.  To date, our limited understanding has stemmed from discovering associations between obesity and asthma phenotypes and candidate gene variants.  For example, several promising genomic areas that contain genes connected with both obesity and asthma (5q23-32, 6p21-23, 11q13, and 12q13-24) have been identified [19, 27, 28, 73, 74] [75, 76].  Only 5 genes have polymorphisms that have been associated with both obesity and asthma [77, 78].  These are: β2-adrenergic receptor gene (ADRB2), the TNFα gene, the lymphotoxin-α (LTA) gene, vitamin D receptor (VDR) gene and PRKCA.  Further interrogation of these and other genetic loci is needed among cohorts with and without obesity and with and without asthma in order to better understand the nature of the obesity-asthma link. 

It is possible that more than one of the above mechanisms (or mechanisms not yet considered) may act together in increasing asthma risk.  We must consider that asthma is a heterogeneous condition with patients varying widely in terms of severity, airflow obstruction, exacerbation triggers, symptom frequency, risk for exacerbation, lung function decline, airflow obstruction, and treatment response.  It is possible that the impact of obesity on asthma-risk varies among individuals, depending on an individual’s genetic factors (gene-environment or gene-gene interactions) or concomitant environmental triggers, such as exposure to environmental tobacco smoke or other pollutants.