Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation

Dixon, Anne E.; Pratley, Richard E.; Forgione, Patrick; Kaminsky, David A.; Whittaker-Leclair, Laurie A.; Griffes, Laurianne A.; Garudathri, Jayanthi; Raymond, Danielle M.; Poynter, Matthew E.; Bunn, Janice Y.; Irvin, Charles G.

doi:10.1016/j.jaci.2011.06.009

Cited by 369 publications

(329 citation statements)

References 47 publications

Supporting

Mentioning

295

Contrasting

Unclassified

Order By: Relevance

“…Macrophages play an important role in the pathogenesis of diseases related to the metabolic syndrome. Prior studies aimed at identifying possible mechanisms that mediate the overweight/obese asthma phenotype have determined that CD4 1 T cells do not appear to play a key role in this association (35). We now propose that alterations in macrophage responses create a unique inflammatory environment in the lungs of overweight/obese subjects with asthma.…”

Section: Discussionmentioning

confidence: 76%

See 1 more Smart Citation

Alveolar Macrophages from Overweight/Obese Subjects with Asthma Demonstrate a Proinflammatory Phenotype

Lugogo¹,

Hollingsworth

Howell³

et al. 2012

Am J Respir Crit Care Med

View full text Add to dashboard Cite

Rationale: Obesity is associated with increased prevalence and severity of asthma. Adipose tissue macrophages can contribute to the systemic proinflammatory state associated with obesity. However, it remains unknown whether alveolar macrophages have a unique phenotype in overweight/obese patients with asthma. Objectives: We hypothesized that leptin levels would be increased in the bronchoalveolar lavage fluid from overweight/obese subjects and, furthermore, that leptin would alter the response of alveolar macrophages to bacterial LPS. Methods: Forty-two subjects with asthma and 46 healthy control subjects underwent research bronchoscopy. Bronchoalveolar lavage fluid from 66 was analyzed for the level of cellular inflammation, cytokines, and soluble leptin. Cultured primary macrophages from 22 subjects were exposed to LPS, leptin, or leptin plus LPS. Cytokines were measured in the supernatants. Measurements and Main Results: Leptin levels were increased in overweight/obese subjects, regardless of asthma status (P ¼ 0.013), but were significantly higher in overweight/obese subjects with asthma. Observed levels of tumor necrosis factor-a were highest in overweight/obese subjects with asthma. Ex vivo studies of primary alveolar macrophages indicated that the response to LPS was most robust in alveolar macrophages from overweight/obese subjects with asthma and that preexposure to high-dose leptin enhanced the proinflammatory response. Leptin alone was sufficient to induce production of proinflammatory cytokines from macrophages derived from overweight/obese subjects with asthma. Conclusions: Ex vivo studies indicate that alveolar macrophages derived from overweight/obese subjects with asthma are uniquely sensitive to leptin. This macrophage phenotype, in the context of higher levels of soluble leptin, may contribute to the pathogenesis of airway disease associated with obesity.Keywords: tumor necrosis factor-a; leptin; innate immunity; lipopolysaccharide; environmental lung disease There is an increased risk of developing asthma in individuals who are overweight and obese (subsequently referred to as overweight/obese) (1-5). The risk of asthma increases steadily with increasing body mass index (BMI) and is higher in women (1, 6). Furthermore, BMI negatively impacts asthma quality of life scores, asthma control scores, severity of exacerbations, and asthma-related hospitalizations (6-9). Together, these studies suggest a role of obesity in the pathogenesis of asthma. However, the mechanisms by which obesity may contribute to airway disease remain poorly understood.Evidence suggests that adipose tissue is metabolically active, participating not only in energy homeostasis but also in inflammation (12). Adipose tissue secretes biologically active cytokines, including tumor necrosis factor (TNF)-a and IL-6, as well as adipokines, including leptin, adiponectin, plasminogen activator inhibitor (PAI)-1, and resistin (10, 11). Obesity is associated with systemic inflammation, which is characterized by elevated serum levels of...

show abstract

Section: Discussionmentioning

confidence: 76%

“…Lack of atopy may play a role in alterations in airway hyperresponsiveness in overweight/obese subjects with asthma (35); however, the underlying mechanisms are poorly understood. Our study was underpowered to detect any differences in macrophage responses based on the presence or absence of atopy.…”

Section: Discussionmentioning

confidence: 99%

Alveolar Macrophages from Overweight/Obese Subjects with Asthma Demonstrate a Proinflammatory Phenotype

Lugogo¹,

Hollingsworth

Howell³

et al. 2012

Am J Respir Crit Care Med

View full text Add to dashboard Cite

show abstract

“…Although asthma is usually associated with inflammation of the lungs, human studies have shown that obesity-related asthma is independent of airway inflammation (44)(45)(46). For example, Dixon and colleagues reported that weight loss by bariatric surgery reduces airway hyperresponsiveness in obese patients with asthma but does not decrease the proportion of lymphocytes in bronchoalveolar lavage fluid or T-cell production of inflammatory cytokines (46).…”

Section: Discussionmentioning

confidence: 99%

“…For example, Dixon and colleagues reported that weight loss by bariatric surgery reduces airway hyperresponsiveness in obese patients with asthma but does not decrease the proportion of lymphocytes in bronchoalveolar lavage fluid or T-cell production of inflammatory cytokines (46). Furthermore, sputum eosinophils are not higher in obese patients with asthma than in nonobese patients with asthma (7,45).…”

Section: Discussionmentioning

confidence: 99%

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

Nie

Jacoby

Fryer

2014

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Obesity is a substantial risk factor for developing asthma, but the molecular mechanisms underlying this relationship are unclear. We tested the role of insulin in airway responsiveness to nerve stimulation using rats genetically prone or resistant to diet-induced obesity. Airway response to vagus nerve stimulation and airway M 2 and M 3 muscarinic receptor function were measured in obeseprone and -resistant rats with high or low circulating insulin. The effects of insulin on nerve-mediated human airway smooth muscle contraction and human M 2 muscarinic receptor function were tested in vitro. Our data show that increased vagally mediated bronchoconstriction in obesity is associated with hyperinsulinemia and loss of inhibitory M 2 muscarinic receptor function on parasympathetic nerves. Obesity did not induce airway inflammation or increase airway wall thickness. Smooth muscle contraction to acetylcholine was not increased, indicating that hyperresponsiveness is mediated at the level of airway nerves. Reducing serum insulin with streptozotocin protected neuronal M 2 receptor function and prevented airway hyperresponsiveness to vagus nerve stimulation in obese rats. Replacing insulin restored dysfunction of neuronal M 2 receptors and airway hyperresponsiveness to vagus nerve stimulation in streptozotocintreated obese rats. Treatment with insulin caused loss of M 2 receptor function, resulting in airway hyperresponsiveness to vagus nerve stimulation in obese-resistant rats, and inhibited human neuronal M 2 receptor function in vitro. This study shows that it is not obesity per se but hyperinsulinemia accompanying obesity that potentiates vagally induced bronchoconstriction by inhibiting neuronal M 2 muscarinic receptors and increasing acetylcholine release from airway parasympathetic nerves.Keywords: hyperinsulinemia; obesity; asthma; airway responsiveness; neural M 2 muscarinic receptor Clinical RelevanceObesity-induced asthma does not respond well to traditional anti-inflammatory therapies, suggesting that it is a unique asthma phenotype. Here we show that hyperinsulinemia causes airway hyperresponsiveness to vagus nerve stimulation in obese rats. In human trachea and in rats, we demonstrate that insulin inhibits M 2 muscarinic receptors on airway parasympathetic nerves, resulting in increased acetylcholine release and increased airway contraction. Because hyperinsulinemia is greater and more prevalent in obese individuals, these data may explain why obese individuals are prone to asthma exacerbations and suggest that anticholinergic drugs may be effective in this specific phenotype of asthma.In the United States, 31% of adults and 15% of children are obese. In obese and overweight individuals, the prevalence of asthma (1-3) and the rate of new-onset asthma have increased (4-6). Obese patients with asthma also have increased severity of illness and reduced effectiveness of steroids compared with nonobese patients with asthma (1, 6, 7). The mechanisms by which obesity predisposes to asthma are unclear, limi...

show abstract

“…Even a moderate weight loss of 5–10% is sufficient to achieve clinical improvements [147]. Therefore, obese asthma patients are recommended to lose weight, possibly with the aid of a dietician.…”

Section: Management Of Severe Asthmamentioning

confidence: 99%

Nordic consensus statement on the systematic assessment and management of possible severe asthma in adults

Porsbjerg

Ulrik

Skjold

et al. 2018

European Clinical Respiratory Journal

View full text Add to dashboard Cite

Although a minority of asthma patients suffer from severe asthma, they represent a major clinical challenge in terms of poor symptom control despite high-dose treatment, risk of exacerbations, and side effects. Novel biological treatments may benefit patients with severe asthma, but are expensive, and are only effective in appropriately targeted patients. In some patients, symptoms are driven by other factors than asthma, and all patients with suspected severe asthma (‘difficult asthma’) should undergo systematic assessment, in order to differentiate between true severe asthma, and ‘difficult-to-treat’ patients, in whom poor control is related to factors such as poor adherence or co-morbidities. The Nordic Consensus Statement on severe asthma was developed by the Nordic Severe Asthma Network, consisting of members from Norway, Sweden, Finland, Denmark, Iceland and Estonia, including representatives from the respective national respiratory scientific societies with the aim to provide an overview and recommendations regarding the diagnosis, systematic assessment and management of severe asthma. Furthermore, the Consensus Statement proposes recommendations for the organization of severe asthma management in primary, secondary, and tertiary care.

show abstract

Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation

Cited by 369 publications

References 47 publications

Alveolar Macrophages from Overweight/Obese Subjects with Asthma Demonstrate a Proinflammatory Phenotype

Alveolar Macrophages from Overweight/Obese Subjects with Asthma Demonstrate a Proinflammatory Phenotype

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

Nordic consensus statement on the systematic assessment and management of possible severe asthma in adults

Contact Info

Product

Resources

About