Increased acetylcholine release in tracheas from allergen-exposed IgE-immune mice

Larsen, Gary L.; Fame, Thomas M.; Renz, Harald; Loader, Joan E.; Graves, J. P.; Hill, Malcolm; Gelfand, EW

doi:10.1152/ajplung.1994.266.3.l263

Cited by 45 publications

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“…Release of ACh from parasympathetic nerves is normally locally controlled by inhibitory neuronal M 2 muscarinic receptors (16)(17)(18)(19)(20), which were initially described on nerves supplying lungs in guinea pigs (19) and have subsequently been described in the parasympathetic nerves supplying the lungs of all species studied thus far (22,(33)(34)(35)(36)(37)(38), including humans. 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).…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…Previous studies show that dysfunctional M 2 receptor is the mechanism of airway hyperresponsiveness in animals that are antigen challenged (26,33), exposed to ozone (25), infected with virus (24), or exposed to organophosphate pesticides (39) and in humans with asthma (21-23). Here we show that insulin also inhibits neuronal M 2 receptor function, resulting in airway hyperresponsiveness to nerve stimulation.…”

Section: Discussionmentioning

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%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Hyperresponsiveness is not due to alterations in the function of the M 3 muscarinic receptors since bronchoconstriction in response to exogenously administered acetylcholine remains unaltered following antigen challenge (8). Rather, hyperresponsiveness appears to be due to the increased release of acetylcholine from the parasympathetic nerves (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Pretreatment with antibody to eosinophil major basic protein prevents hyperresponsiveness by protecting neuronal M2 muscarinic receptors in antigen-challenged guinea pigs.

et al. 1997

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In antigen-challenged guinea pigs there is recruitment of eosinophils into the lungs and to airway nerves, decreased function of inhibitory M 2 muscarinic autoreceptors on parasympathetic nerves in the lungs, and airway hyperresponsiveness. A rabbit antibody to guinea pig eosinophil major basic protein was used to determine whether M 2 muscarinic receptor dysfunction, and the subsequent hyperresponsive

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“…In this model allergen exposure leads to dysfunction of muscarinic receptor 2, which results in an increase in acetylcholine release after electrical field stimulation (EFS) (19). After exclusive aerosolized allergen exposure, allergen-specific IgE and IgG1 are elevated in the serum of exposed mice (20), and the presence of B cells is essential for the development of AHR in this model (21).…”

mentioning

confidence: 99%

Mast Cells, FcεRI, and IL-13 Are Required for Development of Airway Hyperresponsiveness after Aerosolized Allergen Exposure in the Absence of Adjuvant

Taube

Wei

Swasey

et al. 2004

The Journal of Immunology

106

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In certain models of allergic airway disease, mast cells facilitate the development of inflammation and airway hyper-responsiveness (AHR). To define the role of the high affinity IgE receptor (FcεRI) in the development of AHR, mice with a disruption of the α subunit of the high affinity IgE receptor (FcεRI−/−) were exposed on 10 consecutive days to nebulized OVA. Forty-eight hours after the last nebulization, airway responsiveness was monitored by the contractile response of tracheal smooth muscle to electrical field stimulation (EFS). After the 10-day OVA challenge protocol, wild-type mice demonstrated increased responsiveness to EFS, whereas similarly challenged FcεRI−/− mice showed a low response to EFS, similar to nonexposed animals. Further, allergen-challenged FcεRI−/− mice showed less airway inflammation, goblet cell hyperplasia, and lower levels of IL-13 in lung homogenates compared with the controls. IL-13-deficient mice failed to develop an increased response to EFS or goblet cell hyperplasia after the 10-day OVA challenge. We transferred bone marrow-derived mast cells from wild-type mice to FcεRI−/− mice 1 day before initiating the challenge protocol. After the 10-day OVA challenge, recipient FcεRI−/− mice demonstrated EFS-induced responses similar to those of challenged wild-type mice. Transferred mast cells could be detected in tracheal preparations. These results show that FcεRI is important for the development of AHR after an aerosolized allergen sensitization protocol and that this effect is mediated through FcεRI on mast cells and production of IL-13 in the lung.

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Increased acetylcholine release in tracheas from allergen-exposed IgE-immune mice

Cited by 45 publications

References 0 publications

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

Pretreatment with antibody to eosinophil major basic protein prevents hyperresponsiveness by protecting neuronal M2 muscarinic receptors in antigen-challenged guinea pigs.

Mast Cells, FcεRI, and IL-13 Are Required for Development of Airway Hyperresponsiveness after Aerosolized Allergen Exposure in the Absence of Adjuvant

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