Neurotransmitters in Airway Parasympathetic Neurons Altered by Neurotrophin-3 and Repeated Allergen Challenge

Abstract

Changes in airway nerves associated with chronic inflammation may underlie the pathogenesis and symptoms of lower airway diseases, such as asthma. The molecules most likely causing such alterations are neurotrophins (NTs) and/or related neurokines. In several species, including humans, lower airway parasympathetic postganglionic neurons that project axons to airway smooth muscle are either cholinergic or nonadrenergic noncholinergic (NANC), the latter synthesizing vasoactive intestinal peptide and nitric oxide, but not acetylcholine. In guinea pig trachealis smooth muscle, cholinergic nerve terminals arise from ganglionic neurons located near the tracheal smooth muscle, whereas the source of NANC nerve fibers is from neurons in ganglia located in the adjacent myenteric plexus of the esophagus, making this an ideal species to study regulation of parasympathetic neurotransmitter phenotypes. In the present study, we determined that, 48 hours after repeated allergen challenge, the NANC phenotype of airway parasympathetic ganglionic neurons changed to a cholinergic phenotype, and NT-3 mimicked this change. Nerve growth factor, brain-derived neurotrophic factor, leukemia inhibitory factor, or IL-1b had no effect on either phenotype, and they did not induce these neurons to synthesize substance P or tyrosine hydroxylase. These results indicate a role for inflammation and NT-3 in regulating biochemical and anatomical characteristics of principal neurons in adult airway parasympathetic ganglia.

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

“…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).…”

Brain-derived neurotrophic factor in the airways

“…Here, NTs may actually mimic inflammation or other such stimuli. For example, in mice, exogenous NGF enhances airway hyperresponsiveness even in the absence of allergen sensitization and challenge) (Freund-Michel and Frossard, 2008), although this effect does not appear to occur in guinea pigs treated with NGF (Pan et al, 2010). On the other hand, in guinea pigs, BDNF can mimic allergen sensitization by enhancing expression of TRPV1 channels in vagal tracheal cough-causing mechanosensitive neurons of the nodose ganglia, thus enhancing cough reflexes (Lieu et al, 2012).…”

Synaptic and membrane properties of parasympathetic ganglionic neurons innervating mouse trachea and bronchi

“…The parasympathetic nervous system regulates the level and distribution of the signals emanating from the central nervous system and thus plays a pivotal role in the regulation of air flow to the lungs. Because of their peripheral location, parasympathetic nerves may be affected by local inflammation and airway remodeling (18). Although the active and passive (electrophysiological) membrane properties of airway ganglionic neurons have been reported for several mammalian species (13), including humans (8), no studies have focused on mice, a species commonly used in airway asthma and allergy studies (23).…”