Is There Loss of a Protective Muscarinic Receptor Mechanism in Asthma?

Ayala, L. E.; Ahmed, Tahir

doi:10.1378/chest.96.6.1285

Cited by 105 publications

(59 citation statements)

References 15 publications

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“…Loss of M 2 receptor function has been described in asthma (21,23) and is a common feature of many different animal models of airway hyperresponsiveness, including acute infection with parainfluenza virus (24), sensitization and challenge with antigen (26,33), acute exposure to ozone (25), and acute exposure to organophosphate pesticides (39). M 2 muscarinic receptor function is measured in vivo in this study using the selective agonist pilocarpine.…”

Section: Discussionmentioning

confidence: 99%

“…Dysfunctional M 2 muscarinic receptors on airway parasympathetic nerves result in airway hyperresponsiveness in humans with asthma (21)(22)(23) and in animal models of asthma (24)(25)(26). Here we used a polygenic model of diet-induced obesity to test whether obesity increases insulin that subsequently decreases neuronal M 2 receptor function, resulting in airway hyperresponsiveness to vagus nerve stimulation.…”

mentioning

confidence: 99%

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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%

mentioning

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 allergic guinea pigs, the magnitude of the early asthmatic reaction has been reported to correlate significantly with the extent of M 2 autoreceptor dysfunction [142]. M 2 autoreceptors have also been found to be dysfunctional in some but not all asthmatics [143][144][145]. In addition, asthmatics with active viral infections show greater bronchodilatory responses to inhaled anticholinergics, suggesting increased vagal tone [146].…”

Section: Cholinergic Mechanismsmentioning

confidence: 99%

Airway hyperresponsiveness in asthma: lessons from in vitro model systems and animal models

Gosens¹,

Zaagsma²

2008

European Respiratory Journal

107

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Airway hyperresponsiveness (AHR) is a hallmark clinical symptom of asthma. At least two components of AHR have been identified: 1) baseline AHR, which is persistent and presumably caused by airway remodelling due to chronic recurrent airway inflammation; and 2) acute and variable AHR, which is associated with an episodic increase in airway inflammation due to environmental factors such as allergen exposure.Despite intensive research, the mechanisms underlying acute and chronic AHR are poorly understood. Owing to the complex variety of interactive processes that may be involved, in vitro model systems and animal models are indispensable to the unravelling of these mechanisms at the cellular and molecular level.The present paper focuses on a number of translational studies addressing the emerging central role of the airway smooth muscle cell, as a multicompetent cell involved in acute airway constriction as well as structural changes in the airways, in the pathophysiology of airway hyperresponsiveness.

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“…However, it is tempting to speculate that in aspirin-sensitive asthma previous exposure to inflammatory mediators at some critical period has altered coupling of the neuronal M 2 muscarinic receptor to cyclooxygenase. Loss of neuronal M 2 receptor function has been linked to asthma (47,48), and it may be that in some people with asthma the M 2 receptor requires cyclooxygenase to function.…”

Section: Discussionmentioning

confidence: 99%

Viral infection induces dependence of neuronal M2 muscarinic receptors on cyclooxygenase in guinea pig lung.

et al. 1996

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Inhibitory M 2 muscarinic receptors on parasympathetic nerve endings in the lungs decrease release of acetylcholine, inhibiting vagally induced bronchoconstriction. Neuronal M 2 receptor function can be studied using selective agonists and antagonists such as pilocarpine and gallamine. In pathogenfree guinea pigs indomethacin (1 mg/kg) did not alter the effect of either gallamine or pilocarpine, thus in pathogen free animals neuronal M 2 muscarinic receptors function independently of cyclooxygenase products. However, in guinea pigs infected with virus, (which causes temporary loss of M 2 receptor function), and then allowed to recover for 8 wk (to allow recovery of M 2 receptors), indomethacin prevented both gallamine's potentiation and pilocarpine's inhibition of vagally induced bronchoconstriction. This new effect of indomethacin was not blocked by the addition of a 5-lipoxygenase inhibitor, AA861. However, the selective COX II inhibitor, L-745,337, had the same effect as indomethacin. Since exposure to ozone also caused neuronal M 2 receptors to become dependent upon cyclooxygenase the effects of viral infection are likely to be due to inflammation. Thus, despite apparent recovery of normal M 2 receptor function after viral infection or ozone, linkage of these receptors is chronically altered such that they become largely dependent on the activity of COX II. ( J. Clin. Invest. 1996. 98:299-307. )

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Is There Loss of a Protective Muscarinic Receptor Mechanism in Asthma?

Cited by 105 publications

References 15 publications

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

Airway hyperresponsiveness in asthma: lessons from in vitro model systems and animal models

Viral infection induces dependence of neuronal M2 muscarinic receptors on cyclooxygenase in guinea pig lung.

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