Allen C. Myers - US grants

DESCRIPTION (Applicant's abstract): In the airway, the autonomic nervous system controls smooth muscle tone, secretion by glands, and blood flow. Although there is abundant physiological and pharmacological evidence indicating that dysfunction of this autonomic control of the airways contributes to the causes and symptoms of pulmonary diseases such as bronchial asthma and emphysema, little is actually known about the regulation of these nerves. Our long term goal is to provide knowledge of how autonomic tone is regulated in the airway, especially that provided by the parasympathetic nervous system. Control of smooth muscle in the trachea and bronchi is predominantly by nerve fibers that emanate from neuronal cell bodies in parasympathetic ganglia, small clusters of cell bodies located near the airway wall. The parasympathetic tone of the airway smooth muscle is thought to be under the control of the central nervous system where signals are transmitted rhythmically during respiration to the parasympathetic neurons in the airway wall. This signal activates airway parasympathetic ganglia neurons by release of a neurotransmitter which mediates cholinergic synaptic transmission in the ganglia. A separate, but potentially important, form of neural regulation of parasympathetic neurons in the airways is by the so-called local peripheral reflex pathway. In this case, a sensory nerve is activated by changes in the airway and communicates directly with the parasympathetic neuron in the nearby ganglia by releasing neuropeptides from branches of the sensory axon, evoking non-cholinergic synaptic transmission. In other words, this is a sensory-parasympathetic reflex, independent of the central nervous system. A peripheral reflex would thus allow local increases in parasympathetic tone in an airway segment, independent of changes in another segment. This proposal describes experiments that will characterize the mechanistic basis of peripheral reflex activation of airway parasympathetic neurons in human bronchi. This will be done by: 1) measuring sensory input to individual neurons with electrophysiological and anatomical techniques and also determining the neurotransmitter that neuron synthesized; 2) identifying receptors that mediate changes in excitability during reflex activation; 3) determining the biophysical mechanisms of receptor activation, and 4) determining the effects of sensory reflex activation on smooth muscle tone.

In the airway, the autonomic nervous system controls smooth muscle tone, secretion by glands, and blood flow. Although there is abundant physiological and pharmacological evidence indicating that dysfunction of this autonomic control of the airways contributes to the causes and symptoms of pulmonary diseases such as bronchial asthma, chronic obstructive pulmonary disease and emphysema, little is actually known about the regulation of these nerves. Our long term goal is to provide knowledge of how autonomic tone is regulated in the airway, especially that provided by the parasympathetic nervous system. Control of smooth muscle in the trachea and bronchi is predominantly by nerve fibers that emanate from neuronal cell bodies in parasympathetic ganglia, small clusters of cell bodies located near the airway wall. The parasympathetic tone of the airway smooth muscle is thought to be under the control of the central nervous system where signals are transmitted rhythmically during respiration to the parasympathetic neurons in the airway wall. This signal activates airway parasympathetic ganglia neurons by release of a neurotransmitter which mediates cholinergic synaptic transmission in the ganglia. Separate, but potentially important, forms of neural regulation of parasympathetic neurons in the airways are by the so-called local peripheral reflex pathway and the intraganglionic pathways. In the peripherals reflex pathway, a sensory nerve is activated by changes in the airway and communicates directly with the parasympathetic neuron in the nearby ganglia by releasing neuropeptides from branches of the sensory axon, evoking non-cholinergic synaptic transmission. In other words, this is an sensory- parasympathetic reflex, independent of the central nervous system. A peripheral reflex would thus allow local increases in parasympathetic tone in an airway segment, independent of changes in another segment. In the intraganglionic pathway, postganglionic axons leaving a bronchial ganglion serve to innervate, and modulate the function of neighboring ganglia within the airway tree. This proposal describes experiments that will address our central hypothesis, namely that the parasympathetic nerve activity in the airways is shaped by the integration of three separate inputs: 1.) input from the central nervous system {classical cholinergic nicotinic input), 2.) input from the peripheral reflex sensory fibers, and 3.) input from surrounding postganglionic parasympathetic ganglia. We feel that an understanding of the mechanism of this integration is a prerequisite to obtaining knowledge on the mechanisms by which airway neurophysiology is regulated in health and disregulated in disease.

DESCRIPTION (provided by applicant): In the lower airways, the activity of airway smooth muscle, microvasculature, and glands and, consequently, air flow to the lungs, is regulated predominantly by the parasympathetic nervous system. Over the past decade, we have demonstrated that airway parasympathetic ganglionic neurons regulate input (preganglionic) from the central nervous system and how this is altered by neighboring nerves or by inflammation. In this proposal, we will address hypotheses related to how neurotrophins, especially nerve growth factor (NGF), regulate the function of adult airway parasympathetic neurons. Neurotrophins, such as NGF, are increased in the inflamed or infected airways and many symptoms of these diseases (hyperactivity, cough, mucous production) may be related to altered or aberrant functions of the airway nervous system as seen in asthma, chronic obstructive pulmonary disease (COPD), and chronic bronchitis. Neurotrophins function during development, particularly as survival factors, but also as factors involved in differentiation and axon growth. However, both the neurotrophins themselves (NGF, BDNF, NT-4/5 and NT-3) and their high affinity receptors (trkA, trkB and trkC) continue to be expressed post-natally indicating that their function goes far beyond their role in development. We propose to study their role in modulating the airway parasympathetic nervous system in adult animals (mice) and in humans. In Specific Aim 1, we will evaluate the mechanisms by which NGF increase synaptic efficacy at airway parasympathetic ganglia;in this aim, we will directly address hypotheses related to NGF-induced changes in synaptic transmission in mouse and human pig bronchial parasympathetic ganglia as well as hypotheses pertaining to the mechanisms by which neurotrophins modulate the action potential. In Aim 2, we'll determine how neurotrophins regulate the anatomy and neurotransmitter phenotype of airway neurons in mouse and human excitatory cholinergic and inhibitory neurons. In this Aim, we will address hypotheses relating to the changes in dendritic structure that occur with chronic exposure to NGF (and potentially, other neurotrophins), and address the hypothesis that neurotrophins can modulate the function of parasympathetic nerves by altering the neurotransmitter(s) they release. Results from these studies will shed new light on the complex pathophysiology of airway diseases such as asthma and COPD and may ultimately determine new therapeutic treatments for these complex diseases. PROJECT NARRATIVE: Air flows to the lungs through the trachea and bronchi and this airflow is predominately regulated by the parasympathetic nervous system. Certain molecules, call neurotrophins, especially nerve growth factor (NGF), are increased in the inflamed or infected airways and many symptoms of these diseases may be related to changes in parasympathetic nerves that then cause decreased airflow to the lungs as seen in asthma, chronic obstructive pulmonary disease (COPD), and chronic bronchitis. Our research will directly address how NGF and other neurotrophins change the airway parasympathetic nervous system.