Allergic Airway Responses in Obese Mice

Johnston, Richard A.; Zhu, Min; Rivera-Sanchez, Yadira; Lu, Frank Leigh; Theman, Todd A.; Flynt, Lesley; Shore, Stephanie A.

doi:10.1164/rccm.200702-323oc

Cited by 125 publications

(135 citation statements)

References 65 publications

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“…Furthermore, sputum eosinophils are not higher in obese patients with asthma than in nonobese patients with asthma (7,45). Leptin, a proinflammatory adipokine, is also reported to be caused by obesityrelated airway hyperresponsiveness because airway hyperresponsiveness is potentiated in obese mice depleted of leptin (ob/ob mice) or leptin receptors (db/db mice) (47). This may be explained by the finding that leptin deficiency in the central neural system increases parasympathetic nerve activity (48) regardless of whether the bronchi are inflamed.…”

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

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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...

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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

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“…In addition, Th2-targeted therapies have not been as effective as hoped in many clinical trials of asthma (41,67). Furthermore, nonallergic forms of asthma, induced by environmental factors such as air pollutants, viral infection, and obesity, develop independently of Th2 cells (43)(44)(45)(46)(47)68). These observations suggest that asthma is indeed heterogeneous, with distinct phenotypes and with different pathogenic mechanisms operating in different form of disease.…”

Section: The Th2 Hypothesis In Asthmamentioning

confidence: 99%

Th17 cells: new players in asthma pathogenesis

Cosmi

Liotta

Maggi

et al. 2011

Allergy

286

198

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CD4+ T effector lymphocytes are distinguished in different subsets on the basis of their patterns of cytokine secretion. Th1 cells, thank to IFN-c production, are responsible for cell-mediated immunity against intracellular pathogens, Th2 cells, through the production of IL-4, provide some degree of protection against helminthes, and Th17 cells, via IL-17, promote neutrophils recruitment for the clearance of bacteria and fungi. However, beyond their protective role, these T-helper subsets can also be involved in the pathogenesis of several inflammatory diseases. Asthma is an inflammatory disease characterized by different clinical phenotypes. Allergic asthma is the result of an inflammatory process driven by allergen-specific Th2 lymphocytes, whereas Th17 cells are mainly involved in those forms of asthma, where neutrophils more than eosinophils, contribute to the inflammation. The identification in allergic asthma of Th17/Th2 cells, able to produce both IL-4 and IL-17, is in keeping with the observation that different clinical phenotypes can coexist in the same patient. In conclusion, a picture in which different T-cell subpopulations are active in different phase of bronchial asthma is emerging, and the wide spectrum of clinical phenotypes is probably the expression of different cellular characters playing a role in lung inflammation.

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“…Largely through the work of Shore et al, molecular and physiologic characteristics of the murine model of obese asthma are currently being elucidated. 23,[26][27][28][29][30][31][32][33][34] However, assessing lung inflammation and lung responses among obese children remains challenging and limited by current technologies. Studies in children involving bronchodilator responsiveness, bronchoconstricting agonists (e.g., methacholine challenge), and airway inflammatory markers have yet to show the same consistent pattern of hyperresponsiveness that have been demonstrated in mice.…”

Section: If Obesity Leads To Asthma What Is the Mechanism?mentioning

confidence: 99%