Airway tone

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Airway tone, short for airway smooth muscle tone, is the degree of sustained contractile activation of airway smooth muscle. [1] The airways have a tone baseline, and consequently a baseline level of contraction of their smooth musculature. Airway tone is a key determinant of lung function and the presence of respiratory symptoms in obstructive lung diseases such as asthma, where baseline airway tone is elevated. [2] The upper extreme of the spectrum of airway tone represents bronchoconstriction, wherein the airway smooth muscles are significantly contracted, while the lower extreme represents bronchodilatation, wherein the muscles are relatively relaxed.

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While airway tone is related to respiratory airflow and airway caliber insofar as an increase in airway tone decreases airflow due to the airway smooth muscle contraction, the two are not synonymous as airflow is determined by the structural and functional properties of the airways as well as the lung parenchyma in addition to airway tone. [1] [3]

Airway tone and airway resistance are mostly correlated, [4] but adequate upper airway tone is necessary for airflow and airway patency; [5] insufficient upper airway tone during sleep can, for instance, result in obstructive sleep apnea. [6]

Autonomic nervous system signalling

Autonomic nervous system signalling plays a pivotal role in determining airway tone. The innervation of airway smooth musculature varies between the upper and lower airways. [7]

Upper airway tone

The pharynx is innervated by cranial nerves VII, IX, XII, while both the pharynx and the larynx are innervated by the vagus nerve. [7]

Lower airway tone

Lower airway, bronchial, or bronchus tone is mediated both by the innervation of airway smooth musculature and, possibly, also by the innervation of airway mucosal vasculature. Lower airway smooth muscles are mostly only innervated by the vagus nerve. [8] [9]

Cholinergic signalling

Airway smooth muscle is primarily innervated by cholinergic parasympathetic nerves, while its adrenergic sympathetic innervation is sparse to non-existent. Specifically, cholinergic parasympathetic signalling increases the airway tone, meaning the airway tone is proportional to the vagal tone. [8] [10]

Despite this overall airway tone-increasing effect, the individual effects of muscarinic acetylcholine receptors expressed by airway muscle cells, of which there are 5 subtypes, M1 through M5, are ambivalent. M3 receptors directly lead to airway smooth muscle contraction, i.e., an increase in airway tone, while M2 receptors (also) expressed by airway neurons suppress the further release of acetylcholine in a negative feedback loop, wherein cholinergic parasympathetic signalling reduces further cholinergic parasympathetic signalling, which may explain the unexpectedly low effectivity of certain non-selective muscarinic receptor antagonists such as ipratropium bromide. [10]

M2 receptors are less functional in asthma, disrupting the negative feedback which normally reduces airway tone, which may play a role in asthmatic airway hyperresponsiveness. [10]

Adrenergic signalling

As mentioned, adrenergic sympathetic innervation of airway smooth muscle is likely insignificant; however, the sympathetic innervation of the airway mucosal vasculature is significant. Airway muscular vasculature controls the flow of nutrients to the airways, the temperature of the airways, as well as the clearance of insoluble particles in the airways, which may play an important role in the activity of inhaled bronchodilators, thus affecting airway reactivity and airway tone changes in obstructive lung diseases. [9]

Dopaminergic signalling

There is conflicting evidence regarding dopamine's effect on airway tone in vivo, with some studies reporting bronchoconstriction and others bronchodilatation following dopamine inhalation. In one study, dopamine attenuated the increase in airway tone caused by cholinergic signalling, but exacerbated histaminergic bronchoconstriction, while both signals were attenuated in the present study following the administration of intravenous dopamine. [11] Thus, no conclusion can be drawn at this time.

Acute activation of D2 receptors expressed by airway smooth muscle cells inhibits the adenylyl cyclase, lowering cAMP levels, leading to an increase in airway tone. However, their prolonged activation by quinpirole, a D2 and D3 receptor agonist, paradoxically enhances adenylyl cyclase activity, raising cAMP levels, leading to bronchodilatation via phospholipase C and protein kinase C. [12]

Histaminergic signalling

Histamine is a direct bronchoconstrictor that increases airway tone by activating H1 receptors expressed by airway smooth muscle cells. [3]

Bitter taste receptor signalling

Six type 2 (bitter) taste receptors (TAS2Rs) are expressed by airway smooth muscle cells. In the tongue, bitter taste receptors have probably evolved for avoiding the ingestion of plant toxins. In the lungs, bitter taste receptors serve a paradoxically reversed function, causing the relaxation of airway smooth muscle, i.e., a lowering of airway tone. Thus, bitter taste receptor agonists represent promising potential novel bronchodilators. [12] [13]

Phosphodiesterase inhibition

Theophylline's non-selective phosphodiesterase inhibition has been proposed as the mechanism behind its bronchodilatating action. Phosphodiesterases degrade intracellular cAMP, which leads to muscle contraction. Inhibiting phosphodiesterases increases cAMP concentrations in airway smooth muscle cells, lowering airway tone. Adenosine receptor agonism probably does not play a major role in theophylline-induced lowering of airway tone, as inhalation of adenosine actually increases airway tone, though it is probably the cause of theophylline's arrhythmogenicity. [12] [14] [15]

Cysteinyl leukotriene signalling

Like histamine, some cysteinyl leukotrienes, such as leukotriene D4, are direct bronchoconstrictors and increase airway tone by binding to receptors on airway smooth muscle cells. Bronchoconstrictive leukotrienes act via a common cys-LT1 receptor. [3]

Thromboxane signalling

Thromboxane is a direct bronchoconstrictor that acts via the thromboxane receptor on airway smooth muscle cells. [3]

Related Research Articles

<span class="mw-page-title-main">Acetylcholine</span> Organic chemical and neurotransmitter

Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.

<span class="mw-page-title-main">Motor neuron</span> Nerve cell sending impulse to muscle

A motor neuron is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectly control effector organs, mainly muscles and glands. There are two types of motor neuron – upper motor neurons and lower motor neurons. Axons from upper motor neurons synapse onto interneurons in the spinal cord and occasionally directly onto lower motor neurons. The axons from the lower motor neurons are efferent nerve fibers that carry signals from the spinal cord to the effectors. Types of lower motor neurons are alpha motor neurons, beta motor neurons, and gamma motor neurons.

<span class="mw-page-title-main">Autonomic nervous system</span> Division of the nervous system supplying internal organs, smooth muscle and glands

The autonomic nervous system (ANS), sometimes called the visceral nervous system and formerly the vegetative nervous system, is a division of the nervous system that operates internal organs, smooth muscle and glands. The autonomic nervous system is a control system that acts largely unconsciously and regulates bodily functions, such as the heart rate, its force of contraction, digestion, respiratory rate, pupillary response, urination, and sexual arousal. This system is the primary mechanism in control of the fight-or-flight response.

<span class="mw-page-title-main">Parasympathetic nervous system</span> Division of the autonomic nervous system

The parasympathetic nervous system (PSNS) is one of the three divisions of the autonomic nervous system, the others being the sympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of the autonomic nervous system, and sometimes considered an independent system.

<span class="mw-page-title-main">Enteric nervous system</span> Vital system controlling the gastrointestinal tract

The enteric nervous system (ENS) or intrinsic nervous system is one of the three main divisions of the autonomic nervous system (ANS), the other being the sympathetic (SNS) and parasympathetic nervous system (PSNS), and consists of a mesh-like system of neurons that governs the function of the gastrointestinal tract. It is capable of acting independently of the SNS and PSNS, although it may be influenced by them. The ENS is nicknamed the "second brain". It is derived from neural crest cells.

<span class="mw-page-title-main">Bronchiole</span> Passageways by which air passes through the nose or mouth to the alveoli of the lungs

The bronchioles or bronchioli are the smaller branches of the bronchial airways in the lower respiratory tract. They include the terminal bronchioles, and finally the respiratory bronchioles that mark the start of the respiratory zone delivering air to the gas exchanging units of the alveoli. The bronchioles no longer contain the cartilage that is found in the bronchi, or glands in their submucosa.

<span class="mw-page-title-main">Vasodilation</span> Widening of blood vessels

Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel walls are composed of endothelial tissue and a basal membrane lining the lumen of the vessel, concentric smooth muscle layers on top of endothelial tissue, and an adventitia over the smooth muscle layers. Relaxation of the smooth muscle layer allows the blood vessel to dilate, as it is held in a semi-constricted state by sympathetic nervous system activity. Vasodilation is the opposite of vasoconstriction, which is the narrowing of blood vessels.

<span class="mw-page-title-main">Neuroeffector junction</span> Site where a motor neuron releases a neurotransmitter to affect a target cell

A neuroeffector junction is a site where a motor neuron releases a neurotransmitter to affect a target—non-neuronal—cell. This junction functions like a synapse. However, unlike most neurons, somatic efferent motor neurons innervate skeletal muscle, and are always excitatory. Visceral efferent neurons innervate smooth muscle, cardiac muscle, and glands, and have the ability to be either excitatory or inhibitory in function. Neuroeffector junctions are known as neuromuscular junctions when the target cell is a muscle fiber.

<span class="mw-page-title-main">Nucleus ambiguus</span> Group of motor neurons in the brain stem

The nucleus ambiguus is a group of large motor neurons, situated deep in the medullary reticular formation named by Jacob Clarke. The nucleus ambiguus contains the cell bodies of neurons that innervate the muscles of the soft palate, pharynx, and larynx which are associated with speech and swallowing. As well as motor neurons, the nucleus ambiguus contains preganglionic parasympathetic neurons which innervate postganglionic parasympathetic neurons in the heart.

<span class="mw-page-title-main">Myenteric plexus</span> Part of the enteric nervous system

The myenteric plexus provides motor innervation to both layers of the muscular layer of the gut, having both parasympathetic and sympathetic input, whereas the submucous plexus provides secretomotor innervation to the mucosa nearest the lumen of the gut.

<span class="mw-page-title-main">Muscarinic acetylcholine receptor</span> Acetylcholine receptors named for their selective binding of muscarine

Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers. They are mainly found in the parasympathetic nervous system, but also have a role in the sympathetic nervous system in the control of sweat glands.

<span class="mw-page-title-main">Leukotriene</span> Class of inflammation mediator molecules

Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase.

<span class="mw-page-title-main">Glomus cell</span>

Glomus cells are the cell type mainly located in the carotid bodies and aortic bodies. Glomus type I cells are peripheral chemoreceptors which sense the oxygen, carbon dioxide and pH levels of the blood. When there is a decrease in the blood's pH, a decrease in oxygen (pO2), or an increase in carbon dioxide (pCO2), the carotid bodies and the aortic bodies signal the dorsal respiratory group in the medulla oblongata to increase the volume and rate of breathing. The glomus cells have a high metabolic rate and good blood perfusion and thus are sensitive to changes in arterial blood gas tension. Glomus type II cells are sustentacular cells having a similar supportive function to glial cells.

Hypoxic pulmonary vasoconstriction (HPV), also known as the Euler-Liljestrand mechanism, is a physiological phenomenon in which small pulmonary arteries constrict in the presence of alveolar hypoxia. By redirecting blood flow from poorly-ventilated lung regions to well-ventilated lung regions, HPV is thought to be the primary mechanism underlying ventilation/perfusion matching.

<span class="mw-page-title-main">Bronchoconstriction</span> Constriction of the terminal airways in the lungs

Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath.

The cough reflex occurs when stimulation of cough receptors in the respiratory tract by dust or other foreign particles produces a cough, which causes rapidly moving air which usually remove the foreign material before it reaches the lungs. This typically clears particles from the bronchi and trachea, the tubes that feed air to lung tissue from the nose and mouth. The larynx and carina are especially sensitive. Cough receptors in the surface cells (epithelium) of the respiratory tract are also sensitive to chemicals. Terminal bronchioles and even the alveoli are sensitive to chemicals such as sulfur dioxide gas or chlorine gas.

<span class="mw-page-title-main">Vagovagal reflex</span> Reflex circuits in the gastrointestinal tract

Vagovagal reflex refers to gastrointestinal tract reflex circuits where afferent and efferent fibers of the vagus nerve coordinate responses to gut stimuli via the dorsal vagal complex in the brain. The vagovagal reflex controls contraction of the gastrointestinal muscle layers in response to distension of the tract by food. This reflex also allows for the accommodation of large amounts of food in the gastrointestinal tracts.

Bronchodilatation, or bronchodilation, is a reduction in airway resistance caused by the relaxation of airway smooth muscle. It is the opposite of bronchoconstriction.

The basal or basic electrical rhythm (BER) or electrical control activity (ECA) is the spontaneous depolarization and repolarization of pacemaker cells known as interstitial cells of Cajal (ICCs) in the smooth muscle of the stomach, small intestine, and large intestine. This electrical rhythm is spread through gap junctions in the smooth muscle of the GI tract. These pacemaker cells, also called the ICCs, control the frequency of contractions in the gastrointestinal tract. The cells can be located in either the circular or longitudinal layer of the smooth muscle in the GI tract; circular for the small and large intestine, longitudinal for the stomach. The frequency of contraction differs at each location in the GI tract beginning with 3 per minute in the stomach, then 12 per minute in the duodenum, 9 per minute in the ileum, and a normally low one contraction per 30 minutes in the large intestines that increases 3 to 4 times a day due to a phenomenon called mass movement. The basal electrical rhythm controls the frequency of contraction but additional neuronal and hormonal controls regulate the strength of each contraction.

<span class="mw-page-title-main">GR-159897</span> Chemical compound

GR-159897 is a potent and selective NK2 receptor antagonist drug. It has anxiolytic effects in animal models, and also inhibits bronchoconstriction of the airways, which may potentially make it useful in the treatment of asthma.

References

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  2. ↑ Brown, Robert H.; Togias, Alkis (2016-07-01). "Measurement of intraindividual airway tone heterogeneity and its importance in asthma". Journal of Applied Physiology. 121 (1): 223–232. doi:10.1152/japplphysiol.00545.2015. ISSN   8750-7587. PMC   4967252 . PMID   27103654.
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  4. ↑ Hurley, Joshua J.; Hensley, Jeremy L. (2023), "Physiology, Airway Resistance", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   31194340 , retrieved 2023-12-24
  5. ↑ Buchanan, Gordon F. (2013-01-01), Gillette, Martha U. (ed.), "Chapter Eight - Timing, Sleep, and Respiration in Health and Disease", Progress in Molecular Biology and Translational Science, Chronobiology: Biological Timing in Health and Disease, 119, Academic Press: 191–219, doi:10.1016/B978-0-12-396971-2.00008-7, PMID   23899599 , retrieved 2023-12-22
  6. ↑ Strohl, Kingman P.; Butler, James P.; Malhotra, Atul (July 2012). "Mechanical Properties of the Upper Airway". Comprehensive Physiology. 2 (3): 1853–1872. doi:10.1002/cphy.c110053. ISSN   2040-4603. PMC   3770742 . PMID   23723026.
  7. 1 2 Ball, Matthew; Hossain, Mohammad; Padalia, Devang (2023), "Anatomy, Airway", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   29083624 , retrieved 2023-12-24
  8. 1 2 Canning, Brendan J. (September 2006). "Reflex regulation of airway smooth muscle tone". Journal of Applied Physiology. 101 (3): 971–985. doi:10.1152/japplphysiol.00313.2006. ISSN   8750-7587. PMID   16728519. S2CID   26044257.
  9. 1 2 Mazzone, Stuart B.; Lim, Lina H. K.; Wagner, Elizabeth M.; Mori, Nanako; Canning, Brendan J. (November 2010). "Sympathetic nerve-dependent regulation of mucosal vascular tone modifies airway smooth muscle reactivity". Journal of Applied Physiology. 109 (5): 1292–1300. doi:10.1152/japplphysiol.00632.2010. ISSN   8750-7587. PMC   2980371 . PMID   20724568.
  10. 1 2 3 Moulton, Bart C; Fryer, Allison D (May 2011). "Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD". British Journal of Pharmacology. 163 (1): 44–52. doi:10.1111/j.1476-5381.2010.01190.x. ISSN   0007-1188. PMC   3085867 . PMID   21198547.
  11. ↑ Fodor, Gergely H.; Balogh, Adam L.; Sudy, Roberta; Ivankovits-Kiss, Orsolya; Babik, Barna; Petak, Ferenc (2019-01-01). "Dopamine ameliorates bronchoconstriction induced by histaminergic and cholinergic pathways in rabbits". Respiratory Physiology & Neurobiology. 259: 156–161. doi:10.1016/j.resp.2018.10.006. ISSN   1569-9048. PMID   30367990. S2CID   53103857.
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  14. ↑ Jilani, Talha N.; Preuss, Charles V.; Sharma, Sandeep (2023), "Theophylline", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   30085566 , retrieved 2023-12-22
  15. ↑ Barnes, Peter J. (2013-10-15). "Theophylline". American Journal of Respiratory and Critical Care Medicine. 188 (8): 901–906. doi:10.1164/rccm.201302-0388PP. ISSN   1073-449X. PMID   23672674.
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