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Autonomic Neural Control of Intrathoracic Airways

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Abstract

Autonomic neural control of the intrathoracic airways aids in optimizing air flow and gas exchange. In addition, and perhaps more importantly, the autonomic nervous system contributes to host defense of the respiratory tract. These functions are accomplished by tightly regulating airway caliber, blood flow, and secretions. Although both the sympathetic and parasympathetic branches of the autonomic nervous system innervate the airways, it is the later that dominates, especially with respect to control of airway smooth muscle and secretions. Parasympathetic tone in the airways is regulated by reflex activity often initiated by activation of airway stretch receptors and polymodal nociceptors. This review discusses the preganglionic, ganglionic, and postganglionic mechanisms of airway autonomic innervation. Additionally, it provides a brief overview of how dysregulation of the airway autonomic nervous system may contribute to respiratory diseases. © 2012 American Physiological Society. Compr Physiol 2:1241‐1267, 2012.

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Figure 1. Figure 1.

Bronchial innervation during development. (A) The adventitia of a fetal pig (gestation week 5.5) stained with the nonselective neuronal marker PGP 9.5. The plethora of interconnected nerve trunks and maturing ganglia gives rise to a dense plexus of fine fibers covering the airways. Arrow identifies area shown in (B). (B) A magnified view of the area marked by the arrow in (A). The cellular appearance of the forming parasympathetic ganglia is evident, with spherically shaped cells in the ganglia and larger, more spindle‐shaped cell within the large nerve trunk (arrowheads). Figure used with permission from reference .

Figure 2. Figure 2.

Examples of parasympathetic‐driven responses in the airway. (A) Schematic of an experimental setup used to study parasympathetic responses in the airways. The extrathoracic tracheal segment is used for simultaneous recording of blood flow, mucus secretion, and airway smooth muscle tone in vivo. An excitatory amino acid (CNQX) was topically applied to the ventrolateral medullary region to activate preganglionic parasympathetic neurons. The physiological responses to this treatment are illustrated in (B), (C), and (D). (B) Increase in tracheal blood flow (Qt). (C) Rapid increase in tracheal smooth muscle force (Tf). (D) Photograph of mucus secretion using the tantalum hillock technique. Figures adapted, with permission, from reference . Similar parasympathetic responses occur in the intrapulmonary compartment.

Figure 3. Figure 3.

Parasympathetic outflow to the airways. Coronal sections of the brain to the right indicate nuclei that project to preganglionic parasympathetic nuclei. Outflow from preganglionic neurons to parasympathetic ganglion neurons is indicated by dashed lines. Postganglionic axons leave the ganglia and innervate airway smooth muscle glands and blood vessels throughout the airways. LV, lateral ventricle; III, third ventricle; IO, inferior olivary nucleus.

Figure 4. Figure 4.

Nerve plexi and parasympathetic ganglia in the airways. (A) Schematic showing bronchial parasympathetic ganglia located with the extrachrondial and subchondrial plexi. Sections through the cartilage, smooth muscle, and epithelial layers are shown. (B) Camera lucida drawing showing fibers from the extrachondrial nerve trunk of a rabbit bronchi terminating as pericellular baskets on parasympathetic ganglion neurons. The postganglionic axons unite to form a bundle in the subchondrial plexus [adapted, with permission, from reference ].

Figure 5. Figure 5.

Characteristics of human bronchial parasympathetic ganglion neurons. (A) Whole‐mount, intact ganglion showing many neuronal soma (arrow); lighter cells beyond the ganglion are adipocytes. (B) Whole‐mount, intact ganglion showing two neuronal cell bodies (n) with branching dendrites (arrows) and axon (a) stained using neurobiotin. The branching dendrites are indicative of neurons that integrate incoming stimuli. (C) Schematic illustration of ganglionic integration. Neuron “a” receives four action potential inputs from two converging axons, but filters 75% of this input such that a single‐action potential leaves the ganglion. Neuron “b” simply relays the input, and neuron c amplifies the input. (D) Suprathreshold (500 pA) depolarizing stimulus evokes only one action potential in a “phasic” responding neuron. (E) “Tonic” responding neuron evokes multiple action potentials to a similar depolarizing stimulus. (F) Overlay of ten consecutive responses to vagus nerve stimulation evoking nicotinic fast excitatory postsynaptic potentials (fEPSPs) of varying amplitudes (arrows). Threshold indicates action potential generation, while subthreshold indicates fEPSP generation. Nicotine receptor antagonist hexamethonium (10 μmol/L) inhbits vagal nerve‐mediated fEPSPs (at larger concentrations hexamethonium will abolish the fEPSPS in airway ganglia, not shown).

Figure 6. Figure 6.

In guinea pigs, the cholinergic neurons responsible for parasympathetic contractions of smooth muscle are situated in ganglia associated with the airway, whereas NANC neurons responsible for relaxation of airway smooth muscle are associated with the myenteric plexus of the esophagus. This figure provides evidence for separate preganglionic nerves innervating the cholinergic and NANC pathways. (A) Top: a trace of the compound action potential in the guinea pig recurrent laryngeal nerve that innervates the trachea and esophagus. This nerve contains preganglionic parasympathetic axons involved in both contraction and relaxation of the trachealis (in addition to motor axons innervating the larynx and afferent fibers). Three distinct groups of axons can be classified based on their conduction velocities. An Aβ (∼ 20 m/s) wave is first to arise following the shock artifact, followed by slower Aδ (∼ 10 m/s) wave and finally a more diffuse C‐wave (2‐0.4 m/s). Below the trace is the voltage‐response curve for each of the three waves with corresponding arrows. (B) Top: the corresponding voltage response curve for evoking parasympathetic cholinergic contractions and parasympathetic NANC relaxations. The curves show that the contractions (O) are evoked with stimulus intensities that correspond to activation of Aδ preganglionic axons (Δ). Bottom: in contrast, relaxations (□) are evoked only at stimulus intensities consistent with activation of unmyelinated C‐fiber preganglionic axons (▴). Both (Δ) and (▴) were taken from the bottom portion of (A) representing electrical activation of Aδ and C‐fibers, respectively. Data adapted, with permission, from reference .

Figure 7. Figure 7.

Examples of autonomic control of airway smooth muscle. Top: experimental setup to evaluate autonomic regulation of airway smooth muscle in a superfused isolated extrinsically innervated guinea pig tracheal preparation. In this preparation, the esophagus is left attached to the trachea. Middle: a representative tracing of sympathetic and parasympathetic relaxations of the guinea pig trachea. The sympathetic relaxations were evoked by stimulation of the postganglionic fibers in the sympathetic trunk (ST). The sympathetic relaxation is rapid in onset and recovery after a 10‐s stimulation train; note that the relaxation is abolished by treating the trachea with the β‐adrenoceptor antagonist propranolol. Parasympathetic relaxations were evoked by stimulation of preganglionic axons in the recurrent laryngeal nerve (RLN); note that the NANC relaxation is slow to recover from a 10‐s stimulation, is unaffected by propranolol, but is blocked by the ganglionic blocking drug hexamethonium (Hex). The tissue was first contracted with PGF2a and pretreated with atropine to prevent cholinergic contractile response. The response to RLN stimulation is abolished if the esophageal plexus is removed from the preparation (not shown). The scale bar represents 1 and 2 min. Bottom: tracings represent contractions of guinea pig trachea evoked by 10‐s stimulation of vagal preganglionic nerve fibers with square pulses of supramaximal intensity at varying frequencies. The rapid onset contractions are entirely blocked by atropine or ganglionic blockade with Hex (not shown). In (B), the tissue was treated with atropine and contracted with PGF2a so parasympathetic NANC relaxations could be studied. Note that the cholinergic contractions can be evoked by lower frequencies (even a single pulse) than the NANC relaxations. Data taken, with permission, from references , .

Figure 8. Figure 8.

Regulation of basal airway smooth muscle tone. (A) Results showing that airways are tonically constricted due to ongoing parasympathetic cholinergic activity. Matched high‐resolution computed tomography images of canine airways approximately 4 mm in diameter (arrows) during control (left) and after blocking cholinergic muscarinic receptors (right) with 1000 μg/mL ipratropium aerosol . (B) Data adapted, with permission, from a different study showing that the baseline parasympathetic tone in cat airways depends largely on input from the vagal afferent nerves. Note that a 30% of reduction may mean complete relaxation of the airway smooth muscle, and if that occurs with cutting a single vagus nerve, no additional effect is expected by cutting the second nerve. The relative changes in total pulmonary resistance (RL) in cats after unilateral sensory vagotomy (USV), bilateral sensory vagotomy (BSV), or total bilateral vagotomy (TB). Sensory vagotomy involved the careful dissection of the nodose ganglion while sparing the parasympathetic preganglionic fibers .

Figure 9. Figure 9.

Sympathetic outflow to the airways. Cross sections of the brain and spinal cord on the right indicate brain nuclei that project to sympathetic preganglionic neurons. Outflow from preganglionic neurons to sympathetic ganglion neurons is indicated by dashed lines. LV, lateral ventricle; III, third ventricle; IO, inferior olivary nucleus.



Figure 1.

Bronchial innervation during development. (A) The adventitia of a fetal pig (gestation week 5.5) stained with the nonselective neuronal marker PGP 9.5. The plethora of interconnected nerve trunks and maturing ganglia gives rise to a dense plexus of fine fibers covering the airways. Arrow identifies area shown in (B). (B) A magnified view of the area marked by the arrow in (A). The cellular appearance of the forming parasympathetic ganglia is evident, with spherically shaped cells in the ganglia and larger, more spindle‐shaped cell within the large nerve trunk (arrowheads). Figure used with permission from reference .



Figure 2.

Examples of parasympathetic‐driven responses in the airway. (A) Schematic of an experimental setup used to study parasympathetic responses in the airways. The extrathoracic tracheal segment is used for simultaneous recording of blood flow, mucus secretion, and airway smooth muscle tone in vivo. An excitatory amino acid (CNQX) was topically applied to the ventrolateral medullary region to activate preganglionic parasympathetic neurons. The physiological responses to this treatment are illustrated in (B), (C), and (D). (B) Increase in tracheal blood flow (Qt). (C) Rapid increase in tracheal smooth muscle force (Tf). (D) Photograph of mucus secretion using the tantalum hillock technique. Figures adapted, with permission, from reference . Similar parasympathetic responses occur in the intrapulmonary compartment.



Figure 3.

Parasympathetic outflow to the airways. Coronal sections of the brain to the right indicate nuclei that project to preganglionic parasympathetic nuclei. Outflow from preganglionic neurons to parasympathetic ganglion neurons is indicated by dashed lines. Postganglionic axons leave the ganglia and innervate airway smooth muscle glands and blood vessels throughout the airways. LV, lateral ventricle; III, third ventricle; IO, inferior olivary nucleus.



Figure 4.

Nerve plexi and parasympathetic ganglia in the airways. (A) Schematic showing bronchial parasympathetic ganglia located with the extrachrondial and subchondrial plexi. Sections through the cartilage, smooth muscle, and epithelial layers are shown. (B) Camera lucida drawing showing fibers from the extrachondrial nerve trunk of a rabbit bronchi terminating as pericellular baskets on parasympathetic ganglion neurons. The postganglionic axons unite to form a bundle in the subchondrial plexus [adapted, with permission, from reference ].



Figure 5.

Characteristics of human bronchial parasympathetic ganglion neurons. (A) Whole‐mount, intact ganglion showing many neuronal soma (arrow); lighter cells beyond the ganglion are adipocytes. (B) Whole‐mount, intact ganglion showing two neuronal cell bodies (n) with branching dendrites (arrows) and axon (a) stained using neurobiotin. The branching dendrites are indicative of neurons that integrate incoming stimuli. (C) Schematic illustration of ganglionic integration. Neuron “a” receives four action potential inputs from two converging axons, but filters 75% of this input such that a single‐action potential leaves the ganglion. Neuron “b” simply relays the input, and neuron c amplifies the input. (D) Suprathreshold (500 pA) depolarizing stimulus evokes only one action potential in a “phasic” responding neuron. (E) “Tonic” responding neuron evokes multiple action potentials to a similar depolarizing stimulus. (F) Overlay of ten consecutive responses to vagus nerve stimulation evoking nicotinic fast excitatory postsynaptic potentials (fEPSPs) of varying amplitudes (arrows). Threshold indicates action potential generation, while subthreshold indicates fEPSP generation. Nicotine receptor antagonist hexamethonium (10 μmol/L) inhbits vagal nerve‐mediated fEPSPs (at larger concentrations hexamethonium will abolish the fEPSPS in airway ganglia, not shown).



Figure 6.

In guinea pigs, the cholinergic neurons responsible for parasympathetic contractions of smooth muscle are situated in ganglia associated with the airway, whereas NANC neurons responsible for relaxation of airway smooth muscle are associated with the myenteric plexus of the esophagus. This figure provides evidence for separate preganglionic nerves innervating the cholinergic and NANC pathways. (A) Top: a trace of the compound action potential in the guinea pig recurrent laryngeal nerve that innervates the trachea and esophagus. This nerve contains preganglionic parasympathetic axons involved in both contraction and relaxation of the trachealis (in addition to motor axons innervating the larynx and afferent fibers). Three distinct groups of axons can be classified based on their conduction velocities. An Aβ (∼ 20 m/s) wave is first to arise following the shock artifact, followed by slower Aδ (∼ 10 m/s) wave and finally a more diffuse C‐wave (2‐0.4 m/s). Below the trace is the voltage‐response curve for each of the three waves with corresponding arrows. (B) Top: the corresponding voltage response curve for evoking parasympathetic cholinergic contractions and parasympathetic NANC relaxations. The curves show that the contractions (O) are evoked with stimulus intensities that correspond to activation of Aδ preganglionic axons (Δ). Bottom: in contrast, relaxations (□) are evoked only at stimulus intensities consistent with activation of unmyelinated C‐fiber preganglionic axons (▴). Both (Δ) and (▴) were taken from the bottom portion of (A) representing electrical activation of Aδ and C‐fibers, respectively. Data adapted, with permission, from reference .



Figure 7.

Examples of autonomic control of airway smooth muscle. Top: experimental setup to evaluate autonomic regulation of airway smooth muscle in a superfused isolated extrinsically innervated guinea pig tracheal preparation. In this preparation, the esophagus is left attached to the trachea. Middle: a representative tracing of sympathetic and parasympathetic relaxations of the guinea pig trachea. The sympathetic relaxations were evoked by stimulation of the postganglionic fibers in the sympathetic trunk (ST). The sympathetic relaxation is rapid in onset and recovery after a 10‐s stimulation train; note that the relaxation is abolished by treating the trachea with the β‐adrenoceptor antagonist propranolol. Parasympathetic relaxations were evoked by stimulation of preganglionic axons in the recurrent laryngeal nerve (RLN); note that the NANC relaxation is slow to recover from a 10‐s stimulation, is unaffected by propranolol, but is blocked by the ganglionic blocking drug hexamethonium (Hex). The tissue was first contracted with PGF2a and pretreated with atropine to prevent cholinergic contractile response. The response to RLN stimulation is abolished if the esophageal plexus is removed from the preparation (not shown). The scale bar represents 1 and 2 min. Bottom: tracings represent contractions of guinea pig trachea evoked by 10‐s stimulation of vagal preganglionic nerve fibers with square pulses of supramaximal intensity at varying frequencies. The rapid onset contractions are entirely blocked by atropine or ganglionic blockade with Hex (not shown). In (B), the tissue was treated with atropine and contracted with PGF2a so parasympathetic NANC relaxations could be studied. Note that the cholinergic contractions can be evoked by lower frequencies (even a single pulse) than the NANC relaxations. Data taken, with permission, from references , .



Figure 8.

Regulation of basal airway smooth muscle tone. (A) Results showing that airways are tonically constricted due to ongoing parasympathetic cholinergic activity. Matched high‐resolution computed tomography images of canine airways approximately 4 mm in diameter (arrows) during control (left) and after blocking cholinergic muscarinic receptors (right) with 1000 μg/mL ipratropium aerosol . (B) Data adapted, with permission, from a different study showing that the baseline parasympathetic tone in cat airways depends largely on input from the vagal afferent nerves. Note that a 30% of reduction may mean complete relaxation of the airway smooth muscle, and if that occurs with cutting a single vagus nerve, no additional effect is expected by cutting the second nerve. The relative changes in total pulmonary resistance (RL) in cats after unilateral sensory vagotomy (USV), bilateral sensory vagotomy (BSV), or total bilateral vagotomy (TB). Sensory vagotomy involved the careful dissection of the nodose ganglion while sparing the parasympathetic preganglionic fibers .



Figure 9.

Sympathetic outflow to the airways. Cross sections of the brain and spinal cord on the right indicate brain nuclei that project to sympathetic preganglionic neurons. Outflow from preganglionic neurons to sympathetic ganglion neurons is indicated by dashed lines. LV, lateral ventricle; III, third ventricle; IO, inferior olivary nucleus.

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Bradley J. Undem, Carl Potenzieri. Autonomic Neural Control of Intrathoracic Airways. Compr Physiol 2012, 2: 1241-1267. doi: 10.1002/cphy.c110032