Invited Review: Complexity of factors modulating airway narrowing in vivo: relevance to assessment of airway hyperresponsiveness

2003 ◽  
Vol 95 (3) ◽  
pp. 1305-1313 ◽  
Author(s):  
Vito Brusasco ◽  
Riccardo Pellegrino
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscle Activation ◽  
Muscle Tone ◽  
Clinical Settings ◽  
Airway Narrowing ◽  
Geometric Factors ◽  
Airway Caliber ◽  
Airway Response

In vivo, the airway response to constrictor stimuli is the net result of a complex array of factors, some facilitating and some opposing airway narrowing, which makes the interpretation of bronchial challenges far from being straightforward. This review begins with a short description of the complex mechanisms of airway smooth muscle activation and force generation as the starting events for airway narrowing. It then focuses on gain factors modulating airway smooth muscle shortening and on the geometric factors determining the magnitude of reduction in airway caliber in vivo. Finally, in light of the evidence that mechanical modulation of airway smooth muscle tone and airway narrowing is at least as important as the inflammatory contractile mediators in the pathogenesis of airway hyper-responsiveness, the implications for the interpretation of bronchial challenges in clinical settings are discussed.

Inhibition of dihydropyridine-sensitive calcium entry in hypoxic relaxation of airway smooth muscle

1995 ◽  
Vol 268 (2) ◽  
pp. L201-L206 ◽  
Author(s):  
C. Vannier ◽  
T. L. Croxton ◽  
L. S. Farley ◽  
C. A. Hirshman
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscle Tone ◽  
Bay K 8644 ◽  
O2 Concentration ◽  
Voltage Dependent ◽  
Progressive Hypoxia ◽  
Carbamyl Choline

Hypoxia dilates airways in vivo and reduces active tension of airway smooth muscle in vitro. To determine whether hypoxia impairs Ca2+ entry through voltage-dependent channels (VDC), we tested the ability of dihydropyridines to modulate hypoxia-induced relaxation of KCl- and carbamyl choline (carbachol)-contracted porcine bronchi. Carbachol- or KCl-contracted bronchial rings were exposed to progressive hypoxia in the presence or absence of 1 microM BAY K 8644 (an L-type-channel agonist). In separate experiments, rings were contracted with carbachol or KCl, treated with nifedipine (a VDC antagonist), and finally exposed to hypoxia. BAY K 8644 prevented hypoxia-induced relaxation in KCl-contracted bronchi. Nifedipine (10(-5) M) totally relaxed KCl- contracted bronchi. Carbachol-contracted bronchi were only partially relaxed by nifedipine but were completely relaxed when the O2 concentration of the gas was reduced from 95 to 0%. These data indicate that hypoxia can reduce airway smooth muscle tone by limiting entry of Ca2+ through a dihydropyridine-sensitive pathway, but that other mechanisms also contribute to hypoxia-induced relaxation of carbachol-contracted bronchi.

Adaptation to chronic length change in explanted airway smooth muscle

2003 ◽  
Vol 95 (1) ◽  
pp. 448-453 ◽  
Author(s):  
Jahanbakhsh Naghshin ◽  
Lu Wang ◽  
Peter D. Paré ◽  
Chun Y. Seow
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Culture Media ◽  
Length Change ◽  
Functional Change ◽  
Muscle Stiffness ◽  
Airway Narrowing

It has been shown that airway smooth muscle in vitro is able to maintain active force over a large length range by adaptation in the absence of periodic stimulations at 4°C (Wang L, Paré PD, and Seow CY. J Appl Physiol 90: 734–740, 2001). In this study, we show that such adaptation also takes place at body temperature and that long-term adaptation results in irreversible functional change in the muscle that could lead to airway hyperresponsiveness. Rabbit tracheal muscle explants were passively maintained at shortened and in situ length for 3 and 7–8 days in culture media; the length-tension relationship was then examined. The length associated with maximal force generation decreased by 10.5 ± 3.8% (SE) after 3 days and 37.7 ± 8.5% after 7 or 8 days of passive shortening. At day 3, the left shift in the length-tension curve due to adaptation at short lengths was reversible by readapting the muscle at a longer length. The shift was, however, not completely reversible after 7 days. The results suggest that long-term adaptation of airway smooth muscle could lead to increased muscle stiffness and force-generating ability at short lengths. Under in vivo condition, this could translate into resistance to stretch-induced relaxation and excessive airway narrowing.

In vivo loads on airway smooth muscle: the role of noncontractile airway structures

1992 ◽  
Vol 70 (4) ◽  
pp. 602-606 ◽  
Author(s):  
Philip Robinson ◽  
Mitsushi Okazawa ◽  
Tony Bai ◽  
Peter Paré
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscle Activation ◽  
Muscle Length ◽  
Tracheal Cartilage ◽  
Elastic Load ◽  
Muscle Shortening ◽  
Trachealis Muscle

The degree of airway smooth muscle contraction and shortening that occurs in vivo is modified by many factors, including those that influence the degree of muscle activation, the resting muscle length, and the loads against which the muscle contracts. Canine trachealis muscle will shorten up to 70% of starting length from optimal length in vitro but will only shorten by around 30% in vivo. This limitation of shortening may be a result of the muscle shortening against an elastic load such as could be applied by tracheal cartilage. Limitation of airway smooth muscle shortening in smaller airways may be the result of contraction against an elastic load, such as could be applied by lung parenchymal recoil. Measurement of the elastic loads applied by the tracheal cartilage to the trachealis muscle and by lung parenchymal recoil to smooth muscle of smaller airways were performed in canine preparations. In both experiments the calculated elastic loads applied by the cartilage and the parenchymal recoil explained in part the limitation of maximal active shortening and airway narrowing observed. We conclude that the elastic loads provided by surrounding structures are important in determining the degree of airway smooth muscle shortening and the resultant airway narrowing.Key words: elastic loads, tracheal cartilage, airway smooth muscle shortening.

scholarly journals Sympathetic nerve-dependent regulation of mucosal vascular tone modifies airway smooth muscle reactivity

2010 ◽  
Vol 109 (5) ◽  
pp. 1292-1300 ◽  
Author(s):  
Stuart B. Mazzone ◽  
Lina H. K. Lim ◽  
Elizabeth M. Wagner ◽  
Nanako Mori ◽  
Brendan J. Canning
Keyword(s):  
Blood Flow ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Vascular Function ◽  
Adrenergic Receptor ◽  
Muscle Tone ◽  
Mucosal Blood Flow ◽  
Nerve Fibers ◽  
Neurokinin A

The airways contain a dense subepithelial microvascular plexus that is involved in the supply and clearance of substances to and from the airway wall. We set out to test the hypothesis that airway smooth muscle reactivity to bronchoconstricting agents may be dependent on airway mucosal blood flow. Immunohistochemical staining identified vasoconstrictor and vasodilator nerve fibers associated with subepithelial blood vessels in the guinea pig airways. Intravital microscopy of the tracheal mucosal microvasculature in anesthetized guinea pigs revealed that blockade of α-adrenergic receptors increased baseline arteriole diameter by ∼40%, whereas the α-adrenergic receptor agonist phenylephrine produced a modest (5%) vasoconstriction in excess of the baseline tone. In subsequent in vivo experiments, tracheal contractions evoked by topically applied histamine were significantly reduced ( P < 0.05) and enhanced by α-adrenergic receptor blockade and activation, respectively. α-Adrenergic ligands produced similar significant ( P < 0.05) effects on airway smooth muscle contractions evoked by topically administered capsaicin, intravenously administered neurokinin A, inhaled histamine, and topically administered antigen in sensitized animals. These responses were independent of any direct effect of α-adrenergic ligands on the airway smooth muscle tone. The data suggest that changes in blood flow in the vessels supplying the airways regulate the reactivity of the underlying airway smooth muscle to locally released and exogenously administered agents by regulating their clearance. We speculate that changes in mucosal vascular function or changes in neuronal regulation of the airway vasculature may contribute to airways responsiveness in disease.

Airway smooth muscle tone increases airway responsiveness in healthy young adults

2017 ◽  
Vol 312 (3) ◽  
pp. L348-L357 ◽  
Author(s):  
Morgan Gazzola ◽  
Katherine Lortie ◽  
Cyndi Henry ◽  
Samuel Mailhot-Larouche ◽  
David G. Chapman ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscle Tone ◽  
Airway Responsiveness ◽  
High Dose ◽  
Forced Oscillation Technique ◽  
Single High Dose ◽  
Healthy Humans

Force adaptation, a process whereby sustained spasmogenic activation (viz., tone) of airway smooth muscle (ASM) increases its contractile capacity, has been reported in isolated ASM tissues in vitro, as well as in mice in vivo. The objective of the present study was to assess the effect of tone on airway responsiveness in humans. Ten healthy volunteers underwent methacholine challenge on two occasions. One challenge consisted of six serial doses of saline followed by a single high dose of methacholine. The other consisted of six low doses of methacholine 5 min apart followed by a higher dose. The cumulative dose was identical for both challenges. After both methacholine challenges, subjects took a deep inspiration (DI) to total lung capacity as another way to probe ASM mechanics. Responses to methacholine and the DI were measured using a multifrequency forced oscillation technique. Compared with a single high dose, the challenge preceded by tone led to an elevated response measured by respiratory system resistance (Rrs) and reactance at 5 Hz. However, there was no difference in the increase in Rrs at 19 Hz, suggesting a predominant effect on smaller airways. Increased tone also reduced the efficacy of DI, measured by an attenuated maximal dilation during the DI and an increased renarrowing post-DI. We conclude that ASM tone increases small airway responsiveness to inhaled methacholine and reduces the effectiveness of DI in healthy humans. This suggests that force adaptation may contribute to airway hyperresponsiveness and the reduced bronchodilatory effect of DI in asthma.

Reflex regulation of airway smooth muscle tone

2006 ◽  
Vol 101 (3) ◽  
pp. 971-985 ◽  
Author(s):  
Brendan J. Canning
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscle Tone ◽  
Mammalian Species ◽  
Autonomic Nerve ◽  
Autonomic Nerves ◽  
Parasympathetic Nerves ◽  
Afferent Nerves ◽  
Airway Caliber ◽  
Efferent Pathways

Autonomic nerves in most mammalian species mediate both contractions and relaxations of airway smooth muscle. Cholinergic-parasympathetic nerves mediate contractions, whereas adrenergic-sympathetic and/or noncholinergic parasympathetic nerves mediate relaxations. Sympathetic-adrenergic innervation of human airway smooth muscle is sparse or nonexistent based on histological analyses and plays little or no role in regulating airway caliber. Rather, in humans and in many other species, postganglionic noncholinergic parasympathetic nerves provide the only relaxant innervation of airway smooth muscle. These noncholinergic nerves are anatomically and physiologically distinct from the postganglionic cholinergic parasympathetic nerves and differentially regulated by reflexes. Although bronchopulmonary vagal afferent nerves provide the primary afferent input regulating airway autonomic nerve activity, extrapulmonary afferent nerves, both vagal and nonvagal, can also reflexively regulate autonomic tone in airway smooth muscle. Reflexes result in either an enhanced activity in one or more of the autonomic efferent pathways, or a withdrawal of baseline cholinergic tone. These parallel excitatory and inhibitory afferent and efferent pathways add complexity to autonomic control of airway caliber. Dysfunction or dysregulation of these afferent and efferent nerves likely contributes to the pathogenesis of obstructive airways diseases and may account for the pulmonary symptoms associated with extrapulmonary disorders, including gastroesophageal reflux disease, cardiovascular disease, and rhinosinusitis.

scholarly journals Dynamic equilibration of airway smooth muscle contraction during physiological loading

2002 ◽  
Vol 92 (2) ◽  
pp. 771-779 ◽  
Author(s):  
Jeanne Latourelle ◽  
Ben Fabry ◽  
Jeffrey J. Fredberg
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Experimental Method ◽  
Airway Smooth Muscle ◽  
Muscle Length ◽  
Transpulmonary Pressure ◽  
Smooth Muscle Contraction ◽  
Control Force ◽  
Airway Narrowing

Airway smooth muscle contraction is the central event in acute airway narrowing in asthma. Most studies of isolated muscle have focused on statically equilibrated contractile states that arise from isometric or isotonic contractions. It has recently been established, however, that muscle length is determined by a dynamically equilibrated state of the muscle in which small tidal stretches associated with the ongoing action of breathing act to perturb the binding of myosin to actin. To further investigate this phenomenon, we describe in this report an experimental method for subjecting isolated muscle to a dynamic microenvironment designed to closely approximate that experienced in vivo. Unlike previous methods that used either time-varying length control, force control, or time-invariant auxotonic loads, this method uses transpulmonary pressure as the controlled variable, with both muscle force and muscle length free to adjust as they would in vivo. The method was implemented by using a servo-controlled lever arm to load activated airway smooth muscle strips with transpulmonary pressure fluctuations of increasing amplitude, simulating the action of breathing. The results are not consistent with classical ideas of airway narrowing, which rest on the assumption of a statically equilibrated contractile state; they are consistent, however, with the theory of perturbed equilibria of myosin binding. This experimental method will allow for quantitative experimental evaluation of factors that were previously outside of experimental control, including sensitivity of muscle length to changes of tidal volume, changes of lung volume, shape of the load characteristic, loss of parenchymal support and inflammatory thickening of airway wall compartments.

Cigarette smoke-induced bronchoconstriction in dogs: vagal and extravagal mechanisms

1984 ◽  
Vol 57 (4) ◽  
pp. 1261-1270 ◽  
Author(s):  
J. Hartiala ◽  
C. Mapp ◽  
R. A. Mitchell ◽  
R. L. Shields ◽  
W. M. Gold
Keyword(s):  
Smooth Muscle ◽  
Cigarette Smoke ◽  
Airway Smooth Muscle ◽  
Airway Pressure ◽  
Muscle Tone ◽  
Motor Nerve ◽  
Respiratory Center ◽  
Airway Response ◽  
Anesthetized Dogs

We reassessed the severity of cigarette smoke-induced bronchoconstriction and the mechanisms involved in anesthetized dogs. To evaluate the severity of smoke-induced bronchoconstriction, we measured airway pressure and airflow resistance (Rrs, forced oscillation method). We studied the mechanisms in other dogs by measuring airway pressure, central airway smooth muscle tone in tracheal segments in situ, and respiratory center drive by monitoring phrenic motor nerve output, including the role of vagal and extravagal nerves vs. the role of blood-borne materials during inhalation of cigarette smoke. Rrs increased more than fourfold with smoke from one cigarette delivered in two tidal volumes. About half the airway response was due to local effects of smoke in the lungs. The remainder was due to stimulation of the respiratory center, which activated vagal motor efferents to the airway smooth muscle. Of this central stimulation, about half was due to blood-borne materials and the rest to vagal pulmonary afferents from the lungs. We conclude that inhalation of cigarette smoke in dogs causes severe bronchoconstriction which is mediated mainly by extravagal mechanisms.

Effect of lung inflation in vivo on airways with smooth muscle tone or edema

1997 ◽  
Vol 82 (2) ◽  
pp. 491-499 ◽  
Author(s):  
Robert H. Brown ◽  
Wayne Mitzner ◽  
Yonca Bulut ◽  
Elizabeth M. Wagner
Keyword(s):  
Smooth Muscle ◽  
Total Lung Capacity ◽  
Muscle Tone ◽  
Transpulmonary Pressure ◽  
Airway Wall ◽  
Lung Inflation ◽  
Airway Narrowing ◽  
Lung Capacity ◽  
Luminal Area

Brown, Robert H., Wayne Mitzner, Yonca Bulut, and Elizabeth M. Wagner. Effect of lung inflation in vivo on airways with smooth muscle tone or edema. J. Appl. Physiol. 82(2): 491–499, 1997.—Fibrous attachments to the airway wall and a subpleural surrounding pressure can create an external load against which airway smooth muscle must contract. A decrease in this load has been proposed as a possible cause of increased airway narrowing in asthmatic individuals. To study the interaction between the airways and the surrounding lung parenchyma, we investigated the effect of lung inflation on relaxed airways, airways contracted with methacholine, and airways made edematous by infusion of bradykinin into the bronchial artery. Measurements were made in anesthetized sheep by using high-resolution computed tomography to visualize changes in individual airways. During methacholine infusion, airway area was decreased but increased minimally with increases in transpulmonary pressure. Bradykinin infusion caused a 50% increase in airway wall area and a small decrease in airway luminal area. In contrast to airways contracted with methacholine, the luminal area after bradykinin increased substantially with increases in transpulmonary pressure, reaching 99% of the relaxed area at total lung capacity. Thus airway edema by itself did not prevent full distension of the airway at lung volumes approaching total lung capacity. Therefore, we speculate that if a deep inspiration fails to relieve airway narrowing in vivo, this must be a manifestation of airway smooth muscle contraction and not airway wall edema.

ET-1-induced bronchoconstriction is mediated via ETB receptor in mice

1997 ◽  
Vol 83 (1) ◽  
pp. 46-51 ◽  
Author(s):  
Takahide Nagase ◽  
Tomoko Aoki ◽  
Teruaki Oka ◽  
Yoshinosuke Fukuchi ◽  
Yasuyoshi Ouchi
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Function ◽  
Airway Smooth Muscle ◽  
Smooth Muscle Contraction ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Airway Narrowing ◽  
Wall Area ◽  
Significant Difference

Nagase, Takahide, Tomoko Aoki, Teruaki Oka, Yoshinosuke Fukuchi, and Yasuyoshi Ouchi. ET-1-induced bronchoconstriction is mediated via ETB receptor in mice. J. Appl. Physiol. 83(1): 46–51, 1997.—Endothelin (ET)-1 is one of the most potent agonists of airway smooth muscle and can act via two different ET receptor subtypes, i.e., ETA and ETB. To determine the effects of ET-1 on in vivo pulmonary function and which ET receptors are involved in murine lungs, we investigated 1) the effects of ET and sarafotoxin S6c (S6c), a selective ETB agonist, on pulmonary function and 2) the effects of BQ-123 and BQ-788, specific ETA- and ETB-receptor antagonists, on ET-1-induced bronchoconstriction. ICR mice were anesthetized and mechanically ventilated (frequency = 2.5 Hz, tidal volume = 8 ml/kg, positive end-expiratory pressure = 3 cmH2O). Intravenous ET-1, ET-2, and ET-3 increased lung resistance similarly and equipotently, whereas S6c elicited a greater degree of bronchoconstriction. Mice were then pretreated with saline (Sal), BQ-123 (0.2, 1, and 5 mg/kg), or BQ-788 (0.2, 1, and 5 mg/kg) before administration of ET-1 (10−7 mol/kg iv). No dose of BQ-123 blocked ET-1-induced constriction, whereas pretreatment with each dose of BQ-788 significantly inhibited ET-1-induced responses. There were significant differences in morphometrically assessed airway constriction between Sal and BQ-788 and between BQ-123 and BQ-788, whereas no significant difference was observed between Sal and BQ-123. There were no significant morphometric differences in the airway wall area among the three groups. These observations suggest that the ETB- but not ETA-receptor subtype may mediate the changes in murine pulmonary function in response to ET-1. In addition, the ETB-receptor antagonist reduces ET-1-induced airway narrowing by affecting airway smooth muscle contraction in mice.

Sign in / Sign up

Export Citation Format

Share Document