Mechanisms determining cholinergic neural responses in airways of young and mature rabbits

Larsen, Gary L.; Loader, Joan E.; Nguyen, Dee Dee; Fratelli, Cori; Dakhama, Azzeddine; Colasurdo, Giuseppe N.

doi:10.1002/ppul.20060

Cited by 16 publications

(14 citation statements)

References 34 publications

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“…Although AHR to inhaled methacholine (MCh) was not detected in female mice after 10-day ovalbumin (OVA) inhalation in vivo, electrical field stimulation (EFS) in vitro detected altered airway responsiveness. In large part, this EFS response has been attributed to muscarinic receptor dysfunction, activation of neurokinin 1 (NK-1)-dependent pathways, and increased acetylcholine (ACh) release (11,12). In the present study, we identified major differences in the development of MCh-induced alterations in airway resistance (R L ) and dynamic compliance (C dyn ) after 10-day OVA inhalation between male and female mice.…”

mentioning

confidence: 63%

Estrogen Determines Sex Differences in Airway Responsiveness after Allergen Exposure

Matsubara

Swasey

Loader

et al. 2008

Am J Respir Cell Mol Biol

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The female hormone estrogen is an important factor in the regulation of airway function and inflammation, and sex differences in the prevalence of asthma are well described. Using an animal model, we determined how sex differences may underlie the development of altered airway function in response to allergen exposure. We compared sex differences in the development of airway hyperresponsiveness (AHR) after allergen exposure exclusively via the airways. Ovalbumin (OVA) was administered by nebulization on 10 consecutive days in BALB/c mice. After methacholine challenge, significant AHR developed in male mice but not in female mice. Ovariectomized female mice showed significant AHR after 10-day OVA inhalation. ICI182,780, an estrogen antagonist, similarly enhanced airway responsiveness even when administered 1 hour before assay. In contrast, 17b-estradiol dose-dependently suppressed AHR in male mice. In all cases, airway responsiveness was inhibited by the administration of a neurokinin 1 receptor antagonist. These results demonstrate that sex differences in 10-day OVAinduced AHR are due to endogenous estrogen, which negatively regulates airway responsiveness in female mice. Cumulatively, the results suggest that endogenous estrogen may regulate the neurokinin 1-dependent prejunctional activation of airway smooth muscle in allergen-exposed mice.Keywords: estrogen; sex; airway hyperresponsiveness; EFS; neuronal activation Sex differences have been described to play a role in various diseases, including atherosclerosis (1), osteoporosis (2), and certain neurologic disorders (3). Accumulating evidence suggests that hormonal factors are important in the expression of such sex differences at the phenotypic and genotypic levels. A number of epidemiologic and experimental reports suggest that the female hormone estrogen is an important factor in the regulation of airway function and inflammation. Estrogen can prevent cholinergic constriction of asthmatic tracheal rings in vitro (4), and estrogen treatment decreases airway responsiveness to acetylcholine in ovariectomized rats (5). On the other hand, female mice may be more susceptible than male mice to allergen-induced airway inflammation (6-8). The role of estrogen on sex differences in asthma has been the subject of much discussion (9, 10).There are many animal protocols for investigating allergeninduced airway hyperresponsiveness (AHR) and inflammation, with the majority using initial sensitization to allergen together with an adjuvant such as alum. Using this sensitization approach, some mouse studies have suggested a female superiority in the development of allergic airway inflammation (6-8). We examined the development of AHR after allergen exposure exclusively via the airways for 10 consecutive days in the absence of any adjuvant. Although AHR to inhaled methacholine (MCh) was not detected in female mice after 10-day ovalbumin (OVA) inhalation in vivo, electrical field stimulation (EFS) in vitro detected altered airway responsiveness. In large part, this EFS respon...

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confidence: 63%

Estrogen Determines Sex Differences in Airway Responsiveness after Allergen Exposure

Matsubara

Swasey

Loader

et al. 2008

Am J Respir Cell Mol Biol

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“…Thus, one likely mechanism by which IL-1 Ra attenuates ozone-enhanced tracheal smooth muscle responsiveness to EFS is through the downstream inhibition of ozone-increased SP levels in airway neurons. SP enhances cholinergic responsiveness either through a direct effect on sensitivity of airway smooth muscle (Tanaka, et al, 1990) or by enhancing acetylcholine (ACh) release from parasympathetic nerve terminals (Larsen, et al, 2004;Watson, et al, 1993). Our present findings show that IL-1 Ra abolished ozone-enhanced tracheal smooth muscle responsiveness to EFS and to exogenous cholinergic agonists, suggesting that both sensitivity of airway smooth muscle and ACh release from parasympathetic nerve terminals were involved in ozone-induced hyperresponsiveness.…”

Section: Discussionmentioning

confidence: 99%

Interleukin (IL)-1 regulates ozone-enhanced tracheal smooth muscle responsiveness by increasing substance P (SP) production in intrinsic airway neurons of ferret

Barker

Batchelor

et al. 2008

Respiratory Physiology & Neurobiology

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Exposure to ozone induces airway hyperresponsiveness (AHR) mediated partly by SP released from nerve terminals of intrinsic airway neurons. Our recent studies showed that IL-1, an important multifunctional proinflammatory cytokine, increases synthesis and release of SP from intrinsic airway neurons. The purpose of this study is to investigate the possible involvement of endogenous IL-1 in modulating neural responses associated with ozone-enhanced airway responsiveness. Ferrets were exposed to 2 ppm ozone or filtered air for 3 hrs. IL-1 in the bronchoalveolar lavage (BAL) fluid was significantly increased in ozone-exposed animals and responses of tracheal smooth muscle to methacholine (MCh) and electrical field stimulation (EFS) were elevated significantly. Both the SP nerve fiber density in tracheal smooth muscle and the number of SP-containing neurons in airway ganglia were significantly increased following ozone exposure. Pretreatment with IL-1 receptor antagonist (IL-1 Ra) significantly diminished ozone-enhanced airway responses to EFS as well as ozone-increased SP in the airway. To selectively investigate intrinsic airway neurons, segments of ferret trachea were maintained in culture conditions for 24 hrs to eliminate extrinsic contributions from sensory nerves. The segments were then exposed to 2 ppm ozone in vitro for 3 hrs. The changes of ozone-induced airway responses to MCh and EFS, and the SP levels in airway neurons paralleled those observed with in vivo ozone exposure. The ozone-enhanced airway responses and neuronal SP levels were inhibited by pretreatment with IL-1 Ra. These findings show that IL-1 is released during ozone exposure enhances airway responsiveness by modulating SP expression in airway neurons.

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“…Recent evidence indicates that exposures to O 3 during early life (2,4), as well as exposures to a wide range of airway irritants including cigarette smoke (5), respiratory syncytial virus (6), and antigen challenge (7), may alter the normal developmental patterns of airway neural pathways, resulting in enhanced airway smooth muscle responsiveness and inflammation. These findings suggest that normal regulatory mechanisms controlling airway neural development (particularly the production and release of neurotrophins) may be affected by exposure to O 3 or other airway irritants.…”

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confidence: 99%

Role of Nerve Growth Factor in Ozone-Induced Neural Responses in Early Postnatal Airway Development

Hunter¹,

Carrell-Jacks²,

Batchelor³

et al. 2011

Am J Respir Cell Mol Biol

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Airway neural plasticity contributes to the process of airway remodeling in response to airway irritants. However, the mechanisms of neural remodeling in the airways during the early postnatal period, when responses to airway irritation may be most sensitive, have not been characterized. This study used a rat model to examine a possible mechanism of ozone (O 3 )-induced neural hyperresponsiveness during a critical period of developmental, postnatal day (PD) 6, that may be mediated by the neurotrophin nerve growth factor (NGF), resulting in an enhanced release of inflammatory neuropeptide substance P (SP) from airway nerves. Rat pups between PD6-PD28 were killed 24 hours after exposure to O 3 (2 ppm, 3 hours) or filtered air (FA), to establish a timeline of NGF synthesis, or else they were exposed to O 3 or NGF on PD6 or PD21 and re-exposed to O 3 on PD28, and killed on PD29. Measurement endpoints included NGF mRNA in tracheal epithelial cells, NGF protein in bronchoalveolar lavage fluid, airway SP-nerve fiber density (NFD), and SP-positive airway neurons in vagal ganglia. Acute exposure to O 3 increased NGF in bronchoalveolar lavage fluid on PD10 and PD15, and mRNA expression in epithelial cells on PD6, compared with FA controls. NGF protein and mRNA expression in the O 3 -PD6/O 3 -PD28 groups were significantly higher than in the O 3 -PD21/O 3 -PD28 and O 3 -PD6/FA-PD28 groups. NGF-PD6/O 3 -PD28 increased the SP innervation of airway smooth muscle and SP-positive sensory neurons, compared with the NGF-PD21/O 3 -PD28 or NGF-PD6/FA-PD28 groups. NGF enhanced sensory innervation, which may mediate acute responses or prolong sensitivity to O 3 during early life. The model may be relevant in O 3 responses during early childhood.

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Mechanisms determining cholinergic neural responses in airways of young and mature rabbits

Cited by 16 publications

References 34 publications

Estrogen Determines Sex Differences in Airway Responsiveness after Allergen Exposure

Estrogen Determines Sex Differences in Airway Responsiveness after Allergen Exposure

Interleukin (IL)-1 regulates ozone-enhanced tracheal smooth muscle responsiveness by increasing substance P (SP) production in intrinsic airway neurons of ferret

Role of Nerve Growth Factor in Ozone-Induced Neural Responses in Early Postnatal Airway Development

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