Mechanisms of organophosphate insecticide-induced airway hyperreactivity

Fryer, A.D.; Lein, Pamela J.; Howard, Angela S.; Yost, Bethany L.; Beckles, Rondell A.; Jett, David A.

doi:10.1152/ajplung.00343.2003

Cited by 78 publications

(83 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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%

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

Self Cite

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

Section: Discussionmentioning

confidence: 99%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recent animal studies have demonstrated that organophosphates induce airway hyperreactivity, potentially at doses below those causing acetylcholinesterase inhibition (6,7,21). Pesticides may also modulate inflammatory responses to other farm exposures, such as endotoxin and allergens.…”

Section: Discussionmentioning

confidence: 99%

“…Analyses from the Agricultural Health Study (AHS) have demonstrated that pesticide use, particularly that of organophosphate insecticides, is positively associated with wheeze among both farmers (4) and commercial pesticide applicators (5). Animal data indicate that organophosphates induce airway hyperreactivity, potentially at doses below those causing acetylcholinesterase inhibition (6,7).…”

mentioning

confidence: 99%

Pesticides and Atopic and Nonatopic Asthma among Farm Women in the Agricultural Health Study

Hoppin

Umbach²,

London³

et al. 2008

Am J Respir Crit Care Med

140

113

View full text Add to dashboard Cite

Rationale: Risk factors for asthma among farm women are understudied. Objectives: We evaluated pesticide and other occupational exposures as risk factors for adult-onset asthma. Methods: Studying 25,814 farm women in the Agricultural Health Study, we used self-reported history of doctor-diagnosed asthma with or without eczema and/or hay fever to create two case groups: patients with atopic asthma and those with nonatopic asthma. We assessed disease-exposure associations with polytomous logistic regression. Measurements and Main Results: At enrollment (1993)(1994)(1995)(1996)(1997), 702 women (2.7%) reported a doctor's diagnosis of asthma after age 19 years (282 atopic, 420 nonatopic). Growing up on a farm (61% of all farm women) was protective for atopic asthma (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.43-0.70) and, to a lesser extent, for nonatopic asthma (OR, 0.83; 95%CI, 0.68-1.02; P value for difference 5 0.008). Pesticide use was almost exclusively associated with atopic asthma. Any use of pesticides on the farm was associated only with atopic asthma (OR, 1.46; 95% CI, 1.14-1.87). This association with pesticides was strongest among women who had grown up on a farm. Women who grew up on farms and did not apply pesticides had the lowest overall risk of atopic asthma (OR, 0.41; 95% CI, 0.27-0.62) compared with women who neither grew up on farms nor applied pesticides. A total of 7 of 16 insecticides, 2 of 11 herbicides, and 1 of 4 fungicides were significantly associated with atopic asthma; only permethrin use on crops was associated with nonatopic asthma. Conclusions: These findings suggest that pesticides may contribute to atopic asthma, but not nonatopic asthma, among farm women.

show abstract

“…Acute effects of poisoning include central apnea [1][2][3][4], seizures [5,6], bronchorrhea, bronchoconstriction, muscle weakness, myosis, urination, and salivation [7][8][9][10]. The morbidity and mortality from acute OP poisoning is attributed to respiratory failure [11] but the relative contributions of the central and peripheral effects in producing collapse of the respiratory system [12] is unclear.…”

mentioning

confidence: 99%

Pathophysiology of respiratory failure following acute dichlorvos poisoning in a rodent model

Gaspari

Paydarfar

2007

NeuroToxicology

View full text Add to dashboard Cite

INTRODUCTIONOrganophosphate (OP) poisoning produces a cholinergic crisis by blockade of acetylcholinesterase in the central and peripheral nervous systems. Acute effects of poisoning include central apnea [1][2][3][4], seizures [5,6], bronchorrhea, bronchoconstriction, muscle weakness, myosis, urination, and salivation [7][8][9][10]. The morbidity and mortality from acute OP poisoning is attributed to respiratory failure [11] but the relative contributions of the central and peripheral effects in producing collapse of the respiratory system [12] is unclear. The clinical literature emphasizes the peripheral effects contributing to acute pulmonary insufficiency [11,13]. However this does not exclude early mortality in the field due to central apnea [14,15].In this study we used a rodent model to analyze the dynamics of respiratory and cardiovascular collapse during acute OP poisoning. We found that poisoning caused a rapidly lethal central apnea. Central apnea consistently occurred soon after the poisoning but pulmonary insufficiency was more variable in both timing and severity. Mortality was reduced in animals that were sustained solely by artificial ventilation; however most ventilated animals exhibited signs of impaired gas exchange due to pulmonary insufficiency. Our findings support the hypothesis that OP poisoning in this animal model causes a sequential "two hit" insult, with rapid central apnea followed by delayed impairment of pulmonary gas exchange with prominent airway secretions. MATERIALS AND METHODSWe studied 27 male Wistar rats, weighing 275-325 gm (Charles River Laboratories, Wilmington, MA). The University of Massachusetts Medical School Institutional Animal Care and Utilization Committee approved all experimental procedures and protocols. The animal model used in this study is a novel preparation for OP research and the procedures are described in detail below.Corresponding Author: Romolo J Gaspari, MD, MSc, Assistant Professor, Department of Emergency Medicine, University of Massachusetts School of Medicine, 55 Lake Ave North, Worcester, MA 01655, Phone -508-334-7943, Fax -508-421-1490, Gasparir@UMMHC.org, Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Surgical ProceduresSurgical procedures were performed under general anesthesia with 1.5 -2.2% isoflurane (Abbott Labs, North Chicago, IL) titrated to achieve a respiratory rate of 50-60 breaths per minute. All surgical procedures were performed under 100% oxygen. The animals were restrained in a supine position with the head extended and limbs abducted. Adequacy of anesthesia was confir...

show abstract

Mechanisms of organophosphate insecticide-induced airway hyperreactivity

Cited by 78 publications

References 65 publications

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

Pesticides and Atopic and Nonatopic Asthma among Farm Women in the Agricultural Health Study

Pathophysiology of respiratory failure following acute dichlorvos poisoning in a rodent model

Contact Info

Product

Resources

About