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

Hunter, Dawn D.; Carrell-Jacks, Lynnsey A.; Batchelor, Tom P.; Dey, Richard D.

doi:10.1165/rcmb.2010-0345oc

Cited by 17 publications

(24 citation statements)

References 45 publications

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“…These data indicate that SS exposure during early postnatal life increases the level of NGF in lung. We reported recently that NGF was involved in mediating increased substance P expression in ferret airways (39) and that tracheal instillation of NGF during the early postnatal period enhances substance P innervation in rat airway (17). These findings, coupled with the current study, support the possibility that NGF serves as a signaling molecule during inflammatory events in the airways by regulating neuropeptide production.…”

Section: Discussionsupporting

confidence: 87%

“…In an earlier report (40), we showed that airway methacholine responsiveness and SP innervation were increased on PD59 after SS exposure during the early postnatal period but not in the later period. In an entirely different model, Hunter et al (17) showed that ozone exposure in rat pups before PD15 resulted in enhanced SP innervation, but exposures at PD21 and PD28 did not increase SP innervation. Early life exposures to ozone and house dust mite antigen in monkeys also lead to long-lasting effects on airway innervation (19).…”

Section: Discussionmentioning

confidence: 99%

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Early postnatal exposure of mice to side-steam tobacco smoke increases neuropeptide Y in lung

Benders

Hunter

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Wu ZX, Benders KB, Hunter DD, Dey RD. Early postnatal exposure of mice to side-steam tobacco smoke increases neuropeptide Y in lung. Am J Physiol Lung Cell Mol Physiol 302: L152-L159, 2012. First published October, 14, 2011 doi:10.1152/ajplung.00071.2011.-Our recent study showed that prenatal and early postnatal exposure of mice to sidesteam tobacco smoke (SS), a surrogate to environmental tobacco smoke (ETS), leads to increased airway responsiveness and sensory innervation later in life. However, the underlying mechanism initiated in early life that affects airway responses later in life remains undefined. The concomitant increase in nerve growth factor (NGF) after exposures suggests that NGF may be involved the regulation of airway innervation. Since NGF regulates sympathetic nerve responses, as well as sensory nerves, we extended previous studies by examining neuropeptide Y (NPY), a neuropeptide associated with sympathetic nerves. Different age groups of mice, postnatal day (PD) 2 and PD21, were exposed to either SS or filtered air (FA) for 10 consecutive days. The level of NPY protein in lung and the density of NPY nerve fibers in tracheal smooth muscle were significantly increased in the PD2-11SS exposure group compared with PD2-11FA exposure. At the same time, the level of NGF in lung tissue was significantly elevated in the PD2-11SS exposure groups. However, neither NPY (protein or nerves) nor NGF levels were significantly altered in PD21-30SS exposure group compared with the PD21-30FA exposure group. Furthermore, pretreatment with NGF antibody or K252a, which inhibits a key enzyme (tyrosine kinase) in the transduction pathway for NGF receptor binding, significantly diminished SS-enhanced NPY tracheal smooth muscle innervation and the increase in methacholine-induced airway resistance. These findings show that SS exposure in early life increases NPY tracheal innervation and alters pulmonary function and that these changes are mediated through the NGF. airway innervation; asthma; secondhand smoke; neurotrophic factor ENVIRONMENTAL TOBACCO SMOKE (ETS) is an environmental trigger factor that leads to airway inflammation and asthma symptoms in susceptible individuals and animals (25,33,34). Exposure to ETS in utero or during early postnatal development increases the incidence of respiratory illnesses (11,13,28,31,35) later in life. Epidemiological studies (11,13,25,28,(32)(33)(34)(35) show that the probability of developing or exacerbating childhood asthma increases in children of mothers who smoke cigarettes. These results suggest that the prenatal and early postnatal periods are critical periods of developmental sensitivity to cigarette smoke exposure. Indeed, our recent study (40) showed that exposure to side-steam tobacco smoke (SS) during prenatal and early postnatal life produces changes in lung function and airway innervation later in life, supporting the concept of an early life critical period of susceptibility. However, the underlying mechanism initiated by early life exposures that affect lung st...

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Early postnatal exposure of mice to side-steam tobacco smoke increases neuropeptide Y in lung

Benders

Hunter

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…However, a number of recent studies have found that the Trk family of receptors (RTK class VII; Fig. 4) that are responsive to the neurotrophin family of growth factors (238) has novel, diverse roles in ASM, including enhancing [Ca 2ϩ ] i and contractility, particularly in the setting of inflammation (120,200,223,236,239,248,268,344). Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are well recognized in the nervous system for both long-term genomic effects on neuronal growth, differentiation, and survival (181), as well as nongenomic, rapid effects of enhancing [Ca 2ϩ ] i and neurotransmitter release (24,159).…”

Section: Asm [Ca 2ϩ ] I and Contractilitymentioning

confidence: 99%

“…However, the functional role of neurotrophins in the airway are still under investigation. Here, recent data suggest that NGF is released by airway nerves in response to irritants [e.g., ozone (120,322) or cigarette smoke (336)], allergens (346), and infectious agents (38) contributing to irritability and enhanced contractility. NGF can also be derived from airway epithelial cells, for example following viral or bacterial infections (38,222).…”

Section: Asm [Ca 2ϩ ] I and Contractilitymentioning

confidence: 99%

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Prakash

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

177

154

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Prakash YS. Airway smooth muscle in airway reactivity and remodeling: what have we learned? Am J Physiol Lung Cell Mol Physiol 305: L912-L933, 2013. First published October 18, 2013 doi:10.1152/ajplung.00259.2013.-It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca 2ϩ ]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro-vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM "activity" result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis.

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“…The NT, NGF, is increased in asthmatic airways (8) and affects the airway nerve system (9)(10)(11)(12). In mice, levels of NGF have been reported to be increased in infiltrating cells, epithelial cells, and airway smooth muscle after allergic inflammation (13), and is associated with enhanced allergic response (14,15) and airway remodeling (16).…”

Section: Clinical Relevancementioning

confidence: 99%

The Effects of Nerve Growth Factor on Nicotinic Synaptic Transmission in Mouse Airway Parasympathetic Neurons

Weigand

Kwong

Myers

2015

Am J Respir Cell Mol Biol

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In autonomic ganglia, acetylcholine (ACh) is released from preganglionic nerve terminals and binds to nicotinic ACh receptors (nAChRs) on postganglionic neurons, resulting in a brief, short-lived synaptic potential (fast excitatory postsynaptic potential [fEPSP]). Although nerve growth factor (NGF) is known to affect sensory and sympathetic nerves, especially during development, little is known regarding its effect on parasympathetic nerves, especially on adult neurons. Elevated levels of NGF and NGF-mediated neural plasticity may have a role in airway diseases, such as asthma and chronic obstructive pulmonary disease. In this study, we characterize the composition and response of nAChRs in parasympathetic neurons located in lower airways of mice, and note the effects of NGF on fEPSPs and on nicotinic currents. Based on immunohistochemical staining, nAChRs are made up of a-3 and b-4 subunits; in addition, tropomyosin-related kinase A, the receptor for NGF, is also expressed by the neurons. Vagus nerve evoked fEPSPs and inward currents evoked by a nicotinic receptor agonist (1,1-dimethyl-4-phenylpiperazinium) were increased by NGF. NGF also affected the action potential after hyperpolarization. These studies were done in mice, which are routinely used to study airway diseases, such as asthma, where the allergen-induced contraction of airway smooth muscle has a well-defined parasympathetic cholinergic component.Keywords: nerves; parasympathetic; cholinergic; bronchoconstriction; asthma Clinical RelevanceIn chronic allergy, asthma, and chronic obstructive pulmonary disease, the airways are remodeled with increased growth or number of infiltrating cells, fibroblasts, smooth muscle, and glands. All of these are potential sources of neurotrophins and related neurotrophic factors that may affect nearby parasympathetic nerves. The long-term objective of our research is to determine the mechanism of action of neuronal growth factors that affect the airway nervous system, particularly autonomic parasympathetic neurons. Results of our research should provide critical insights into how neurotrophic growth factors cause dysfunction of parasympathetic neurons, especially during airway inflammation and disease.Neurons in airway parasympathetic ganglia function to control and distribute the signals emanating from the central nervous system (CNS) and are thus pivotal in regulating airway smooth muscle tone and airway caliber (1) In the parasympathetic pathway, preganglionic nerves from the CNS brainstem terminate at synapses within parasympathetic ganglia near the airway wall; postganglionic axons exit these ganglia and innervate the entire airway tree, including bronchioles (2). Nicotinic acetylcholine (ACh) receptors (nAChRs) are known to mediate fast synaptic transmission in all autonomic ganglia; ACh, released from preganglionic nerve terminals, binds to nAChRs on postganglionic neurons, resulting in a brief, short-lived synaptic potential (fast excitatory postsynaptic potential [fEPSP]). Although much is known about...

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

Cited by 17 publications

References 45 publications

Early postnatal exposure of mice to side-steam tobacco smoke increases neuropeptide Y in lung

Early postnatal exposure of mice to side-steam tobacco smoke increases neuropeptide Y in lung

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

The Effects of Nerve Growth Factor on Nicotinic Synaptic Transmission in Mouse Airway Parasympathetic Neurons

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