Effect of leptin on allergic airway responses in mice

Shore, Stephanie A.; Schwartzman, Igor N.; Mellema, Matthew S.; Flynt, Lesley; Imrich, Amy; Johnston, Richard A.

doi:10.1016/j.jaci.2004.10.007

Cited by 303 publications

(271 citation statements)

References 42 publications

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“…Leptin is associated with increased airway hyperresponsiveness and serum IgE in murine models (16). In humans, higher serum leptin levels are associated with the presence of asthma, an effect that is more prominent in women.…”

mentioning

confidence: 97%

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

Lugogo¹,

Hollingsworth

Howell³

et al. 2012

Am J Respir Crit Care Med

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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...

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mentioning

confidence: 97%

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

Lugogo¹,

Hollingsworth

Howell³

et al. 2012

Am J Respir Crit Care Med

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“…Previous studies have investigated the functional role of adiponectin and leptin in asthma: in allergic mouse models of asthma, leptin increases and adiponectin decreases airway reactivity (22,23). We found a significant relationship between visceral fat leptin expression and airway reactivity.…”

Section: Discussionmentioning

confidence: 48%

“…Although this association obviously does not show that leptin causes AHR, multiple factors could contribute to AHR in obesity (17). Shore and coworkers (22) have shown that leptin infusion increases airway reactivity in a mouse model of allergic asthma, and that this is not related to increased allergic airway inflammation. This suggests that leptin and leptin receptor signaling may affect airway function through mechanisms other than allergic airway inflammation.…”

Section: Discussionmentioning

confidence: 95%

Obesity and Asthma

Sideleva¹,

Suratt²,

Black³

et al. 2012

Am J Respir Crit Care Med

289

159

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Rationale: Obesity is a major risk factor for asthma; the reasons for this are poorly understood, although it is thought that inflammatory changes in adipose tissue in obesity could contribute to airway inflammation and airway reactivity in individuals who are obese. Objectives: To determine if inflammation in adipose tissue in obesity is related to late-onset asthma, and associated with increased markers of airway inflammation and reactivity. Methods: We recruited a cohort of obese women with asthma and obese control women. We followed subjects with asthma for 12 months after bariatric surgery. We compared markers in adipose tissue and the airway from subjects with asthma and control subjects, and changes in subjects with asthma over time. Measurements and Main Results: Subjects with asthma had increased macrophage infiltration of visceral adipose tissue (P , 0.01), with increased expression of leptin (P , 0.01) and decreased adiponectin (p , 0.001) when controlled for body mass index. Similar trends were observed in subcutaneous adipose tissue. Airway epithelial cells expressed receptors for leptin and adiponectin, and airway reactivity was significantly related to visceral fat leptin expression (rho ¼ 20.8; P , 0.01). Bronchoalveolar lavage cytokines and cytokine production from alveolar macrophages were similar in subjects with asthma and control subjects at baseline, and tended to increase 12 months after surgery. Conclusions: Obesity is associated with increased markers of inflammation in serum and adipose tissue, and yet decreased airway inflammation in obese people with asthma; these patterns reverse with bariatric surgery. Leptin and other adipokines may be important mediators of airway disease in obesity through direct effects on the airway rather than by enhancing airway inflammation.

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“…58 Leptin is pro-inflammatory and pre-treatment with leptin during allergen challenge of sensitized mice increased the allergen-induced AHR without an influx of eosinophils and T helper type 2 cytokine expression. 59 High levels of leptin have been associated with an increased lifetime prevalence of asthma, especially in non-atopic asthma. 60 In asthmatic patients, serum levels of leptin are high, independently from obesity, 61,62 leading one to consider that leptin may contribute to the inflammatory cascade typical of asthma or it could be the result of the systemic state of inflammation present in the disease.…”

Section: Mechanical Airway Changes In Obesitymentioning

confidence: 99%

Asthma and obesity in childhood: on the road ahead

2010

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Epidemiological data show a link between asthma and obesity, suggesting many different mechanisms that may underlie the association. However, diagnosis of asthma is often self-reported by patients or caregivers. Definition of asthma is crucial, particularly in childhood. Obesity can be associated with symptoms commonly attributed to asthma, such as wheezing, dyspnoea and sleep apnoea. Obese subjects are less fit and may have more frequent bouts of breathlessness on exertion accompanied by an exaggerated symptom perception. Therefore, the link between the two diseases should be analysed by focusing not only on reported diagnosis of asthma but also on objective markers that can better characterize the asthma phenotype. These markers should include lung function parameters, bronchial hyper-reactivity, atopic sensitization and indices of lung inflammation. As we look back and move forward, a multidisciplinary approach is increasingly necessary to understand the complexity of obesity and asthma, keeping in mind that diet and exercise could influence both diagnosis and treatment. In the meantime, in clinical settings, physicians should be cautious about diagnosing asthma in obese children on the basis of selfreported symptoms alone and should confirm the diagnosis by using objective measurements and marker evaluations that can better identify asthma phenotype and exclude overdiagnosis.

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Effect of leptin on allergic airway responses in mice

Cited by 303 publications

References 42 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

Obesity and Asthma

Asthma and obesity in childhood: on the road ahead

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