Regulation Of Bronchomotor Tone Research Articles

Retinoic acid signaling is essential for airway smooth muscle homeostasis.

Airway smooth muscle (ASM) is a dynamic and complex tissue involved in regulation of bronchomotor tone, but the molecular events essential for the maintenance of ASM homeostasis are not well understood. Observational and genome-wide association studies in humans have linked airway function to the nutritional status of vitamin A and its bioactive metabolite retinoic acid (RA). Here, we provide evidence that ongoing RA signaling is critical for the regulation of adult ASM phenotype. By using dietary, pharmacologic, and genetic models in mice and humans, we show that (a) RA signaling is active in adult ASM in the normal lung, (b) RA-deficient ASM cells are hypertrophic, hypercontractile, profibrotic, but not hyperproliferative, (c) TGF-β signaling, known to cause ASM hypertrophy and airway fibrosis in human obstructive lung diseases, is hyperactivated in RA-deficient ASM, (d) pharmacologic and genetic inhibition of the TGF-β activity in ASM prevents the development of the aberrant phenotype induced by RA deficiency, and (e) the consequences of transient RA deficiency in ASM are long-lasting. These results indicate that RA signaling actively maintains adult ASM homeostasis, and disruption of RA signaling leads to aberrant ASM phenotypes similar to those seen in human chronic airway diseases such as asthma.

Noncontractile Functions of Airway Smooth Muscle Cells in Asthma

Although pivotal in regulating bronchomotor tone in asthma, airway smooth muscle (ASM) also modulates airway inflammation and undergoes hypertrophy and hyperplasia, contributing to airway remodeling in asthma. ASM myocytes secrete or express a wide array of immunomodulatory mediators in response to extracellular stimuli, and in chronic severe asthma, increases in ASM mass may render the airway irreversibly obstructed. Although the mechanisms by which ASM secretes cytokines and chemokines are the same as those regulating immune cells, there exist unique ASM signaling pathways that may provide novel therapeutic targets. This review provides an overview of our current understanding of the proliferative as well as the synthetic properties of ASM.

Airway smooth muscle as an immunomodulatory cell

Although pivotal in regulating bronchomotor tone in asthma, airway smooth muscle (ASM) also modulates airway inflammation in asthma. ASM myocytes secrete or express a wide array of immunomodulatory mediators in response to extracellular stimuli, and in chronic severe asthma, increases in ASM mass may also render the airway irreversibly obstructed. Although the mechanisms by which ASM secretes cytokines and chemokines are shared with those regulating immune cells, there exist unique ASM signaling pathways that may provide novel therapeutic targets. This review provides an overview of our current understanding of the proliferative as well as synthetic properties of ASM.

Is Airway Smooth Muscle the “Missing Link” Modulating Airway Inflammation in Asthma?

Airway smooth muscle (ASM) plays a central role in regulating bronchomotor tone in patients with asthma. New evidence, however, suggests that ASM may also orchestrate and perpetuate airway inflammation by promoting the recruitment, activation, and trafficking of inflammatory cells in the airways. This review addresses the immunomodulatory function of ASM and highlights how such function may have therapeutic implications in the management of asthma.

Cellular and molecular mechanisms regulating airway smooth muscle physiology and pharmacology

Airway smooth muscle (ASM) in asthma is the pivotal cell regulating bronchomotor tone. Recent evidence suggests that ASM may also modulate airway inflammation and perpetuate airway remodeling. A variety of signaling pathways regulate ASM cytokine-chemokine secretion as well as cell adhesion molecule expression. Interestingly, these signaling pathways appear to be disparate from those of trafficking leukocytes. In this review, excitation-contraction coupling as well as synthetic function of ASM, defined as the ability to secrete immunomodulatory cytokines and chemokines and to express cell surface receptors that are important in cell adhesion and leukocyte activation, will be reviewed. Pharmacologic approaches to modify the synthetic function of ASM and how altered synthetic function may contribute to airway remodeling will also be defined.

Protease-activated receptor 2 in regulation of bronchomotor tone: Effect of tobacco smoking

Protease-activated receptors are G protein-coupled receptors activated by serine-proteases. Protease-activated receptor 2 is involved in the regulation of airway smooth muscle tone but its effects vary according to species and experimental conditions. We determined the effects of protease-activated receptor 2 activation on smooth muscle tone and airway reactivity to histamine in guinea pigs and smoking or non-smoking humans. The effects of trypsin and protease-activated receptor activating peptide on the isometric tension and response to histamine of guinea pig tracheal and human bronchial rings were studied. Human tissues were obtained from 6 smokers and 4 non-smokers. We assessed the effects of epithelial removal, inhibitors of cyclooxygenases, nitric oxide synthases, neutral endopeptidase and antagonists of acetylcholine, histamine, bradykinin and tachykinin receptors. Bronchomotor responses to protease-activated receptor 2 activation were variable in guinea pig, in half of animals PAR2 activation induced smooth muscle relaxation through the epithelial release of prostanoids but not of nitric oxide. In human airways, protease-activated receptor 2 activation reduced responsiveness to histamine in bronchial rings from smokers but increased responsiveness in bronchi from non-smokers. This study demonstrates an influence of tobacco smoking on the effect of protease-activated receptor 2 activation on airway responsiveness in humans, with an increased protection against histamine-induced contractions, probably through an increased epithelial release of prostanoids. The role of airway protease-activated receptor 2 may be to maintain smooth muscle tone homeostasis.

Airway smooth muscle: contraction and beyond

Airway smooth muscle (ASM), an important tissue involved in the regulation of bronchomotor tone, exists in the trachea and in the bronchial tree up to the terminal bronchioles. The physiological relevance of ASM in healthy airways remains unclear. Evidence, however, suggests that ASM undergoes marked phenotypic modulation in lung development and in disease states such as asthma, chronic bronchitis and emphysema. The shortening of ASM regulates airway luminal diameter and modulates airway resistance, which can be augmented by cytokines as well as extracellular matrix alterations. ASM may also serve immunomodulatory functions, which are mediated by the secretion of pro-inflammatory mediators such as cytokines and chemokines. In addition, ASM mass increases in chronic airway diseases and may represent either a pathologic or an injury-repair response due to chronic inflammation. This review will present evidence that ASM, a “passive” contractile tissue, may become an “active participant” in modulating inflammation in chronic lung diseases.Cell facts•Found in the trachea and along the bronchial tree.•Critically important in regulating bronchomotor tone of the airways.•Differentiation state is associated with the expression of various “contractile proteins.”•Displays phenotypic modulation of mechanical, synthetic and proliferative responses.•Secretes cytokines, chemokines and extracellular matrix proteins.•May serve as a potential new target for the treatment of chronic lung diseases.

Pulmonary neuroendocrine cells (PNEC) and neuroepithelial bodies (NEB): chemoreceptors and regulators of lung development.

The airway and alveolar epithelia contain pulmonary neuroendocrine cells whose structure indicates an endocrine function. They are also in contact with sensory nerve fibres. These cells often aggregate into distinct corpuscles-neuroepithelial bodies-and carry membrane receptors sensitive to a number of stimuli, including hypoxia and nicotine. They synthesise, store and release a number of bioactive substances such as serotonin, calcitonin gene-related peptide and the mitogen bombesin. When these are released they contribute to redistribution of pulmonary blood flow, regulation of bronchomotor tone, modulation of the immune response, stimulation of sensory nerve fibres and regulation of lung growth and development. Pulmonary neuroendocrine cells and neuroepithelial bodies seem to be most important in the fetal and neonatal lung as regulators of airway development and hypoxia-sensitive chemoreceptors. There is a link between these cells and specific types of lung cancer and their involvement in lung and paediatric pathology may be profound.

The lung HETEs (and EETs) up.

Arachidonic acid metabolites of the cyclooxygenase and lipoxygenase pathways have a variety of important lung functions. Recent observations indicate that cytochrome P-450 (P-450) monooxygenases are also expressed in the lung, localized to specific pulmonary cell types (e.g., epithelium, endothelium, and smooth muscle), and may modulate critical lung functions. This review summarizes recent data on the presence and biological activity of P-450-derived eicosanoids in the pulmonary vasculature and airways, including effects on pulmonary vascular and bronchial smooth muscle tone and airway epithelial ion transport. We hypothesize a number of potential functions of P-450-derived arachidonate metabolites in the lungs such as contribution to hypoxic pulmonary vasoconstriction, regulation of bronchomotor tone, control of the composition of airway lining fluid, and limitation of pulmonary inflammation. Finally, we describe a number of emerging technologies, including congenic and transgenic strains of experimental animals, P-450 isoform-specific inhibitors and inhibitory antibodies, eicosanoid analogs, and vectors for delivery of P-450 cDNAs and antisense oligonucleotides. These tools will facilitate further studies on the contribution of endogenously formed P-450 eicosanoid metabolites to lung function, under both normal and pathological conditions.

Reduced intracellular magnesium concentrations in asthmatic patients.

Magnesium is important in the regulation of bronchomotor tone, and low dietary intake of magnesium has been associated with airway hyperresponsiveness in epidemiological studies. The concentration of magnesium in serum, erythrocytes and urine in 49 patients with asthma (29 males, aged 15-65 yrs) and in 25 normal subjects (15 males, aged 17-36 yrs) was studied by atomic absorption. Magnesium concentrations were significantly lower in erythrocytes and urine in both atopic (n = 26) and nonatopic (n = 23) asthmatic patients as compared with the control group, whereas serum concentrations did not differ. The concentration of magnesium in erythrocytes was not related to the degree of airway obstruction as measured by forced expiratory volume in one second (FEV1) but was significantly correlated with airway hyperresponsiveness measured as the provocative concentration causing a 20% fall in FEV1 to inhaled acetylcholine (r = 0.64; p<0.05). In addition, a magnesium tolerance test showed increased retention of magnesium (58.9% of administered dose in asthmatic patients compared with 8.9% in normal subjects, p<0.05). In conclusion, the low cellular concentration of magnesium may be associated with airway hyperresponsiveness in asthmatic patients.

Binding of [ 3H][D-Ala 2, MePhe 4, Gly-ol 5] Enkephalin, [ 3H][D-Pen 2, D-Pen 5]Enkephalin, and [ 3H]U-69,593 to Airway and Pulmonary Tissues of Normal and Sensitized Rats

Bhargava, H. N., V. M. Villar, J. Cortijo and E. J. Morcillo. Binding of [ 3H][D-Ala 2, MePhe 4, Gly-ol 5]enkephalin, [ 3H][D-Pen 2, D-Pen 5]enkephalin, and [ 3H]U-69,593 to airway and pulmonary tissues of normal and sensitized rats. Peptides 18(10) 1603–1608, 1997.—The role of endogenous opioid peptides in the regulation of bronchomotor tone, as well as in the pathophysiology of asthma is uncertain. We have studied the binding of highly selective [ 3H]labeled ligands of μ-([D-Ala 2, MePhe 4, Gly-ol 5]enkephalin; DAMGO), δ ([D-Pen 2, D-Pen 5]enkephalin; DPDPE), and κ-(U-69,593) opioid receptors to membranes of trachea, main bronchus, lung parenchyma and pulmonary artery obtained from normal (unsensitized) and actively IgE-sensitized rats acutely challenged with the specific antigen. [ 3H]DAMGO, [ 3H]DPDPE and [ 3H]U-69,593 bound to membranes of normal and sensitized tissues at a saturable, single high-affinity site. The rank order of receptor densities in normal tissues was δ- ≥ κ- ≥ μ-, with lung parenchyma exhibiting the greatest binding capacity for δ- and μ- receptors compared to the other regions examined. The K d values showed small differences between ligands and regions tested. The μ- and δ-opioid receptor densities were decreased in sensitized main bronchus and lung parenchyma, respectively, compared to normal tissues. By contrast, κ-opioid receptor density was augmented in sensitized lung parenchyma but an increase in K d values was also observed. These differential changes in the density and affinity of opioid receptor types may be related to alterations in endogenous opioid peptides during the process of sensitization.

Human Fetal Tracheal Smooth Muscle Produces Spontaneous Electromechanical Oscillations That Are Ca^2+ Dependent and Cholinergically Potentiated

Although the electromechanical properties of, and the cholinergic innervation to adult airway smooth muscle has been extensively studied, the little information is available on developing human airway smooth muscle, and the role of cholinergic mechanisms in regulating bronchomotor tone. A total of 7 tracheae obtained at the time of elective abortion and between 12-16 weeks of gestational development were used in this study. For each trachea, muscle tension and transmembrane potentials were measured simultaneously using an isometric force transducer and a standard 3-M KCl-filled glass microelectrode. All preparations showed spontaneous electrical oscillations approximately 8 mV in amplitude, which could be increased using electrical field stimulation, or exogenously applied acetylcholine. This was accompanied by a corresponding increase in muscle tension. Atropine (0.1 microM) abolished this potentiation, but had no apparent effect on the oscillations. Slow-wave activity was completely suppressed in the absence of extracellular Ca2+, or in the presence of verapamil (1 microM) or quinidine (1 microM). It appears that these oscillations of membrane potential may be potentiated by cholinergic mechanisms which regulate cell membrane ion channels, thus serving to change excitability in a rhythmic manner.

Nonadrenergic bronchodilation induced by high concentrations of sulfur dioxide

SO2 is an environmental pollutant known to elicit bronchospasm in susceptible subjects. We observed that brief exposure of artificially bronchoconstricted cats to high concentrations of SO2 induces a bronchodilator response. This study assessed the characteristics of this response and examined various mechanisms that might underlie it. Cats were anesthetized with diallylbarbital-urethan, and airway smooth muscle tone, measured by lung resistance and dynamic lung compliance, was elevated with a continuous infusion of 5-hydroxytryptamine. Administration of 10 breaths of SO2 via a tracheostomy induced concentration-dependent bronchodilation in the range 100-1,000 parts/million. Only infrequently was bronchoconstriction observed before bronchodilation. SO2-induced bronchodilator responses were unaffected by pretreatment with intravenous atropine or propranolol, establishing them as nonadrenergic noncholinergic (NANC) in origin. Neither the ganglionic blocking agent hexamethonium nor the nerve toxin tetrodotoxin influenced the SO2-induced bronchodilation, thus excluding a role for central or local autonomic reflexes in the response. Efforts to modulate the response by pretreatment with the cyclooxygenase inhibitor indomethacin or the mediator release inhibitor cromolyn sodium also were unsuccessful. Administration of acidic aerosols failed to mimic the SO2-induced bronchodilator response. Although the mechanism whereby SO2 induces bronchodilation under these experimental conditions remains unclear, release of a NANC inhibitory transmitter from a neural, epithelial, or other cellular source via a mechanism insensitive to both tetrodotoxin and cromolyn is a distinct possibility. An intrinsic NANC inhibitory system may exist in feline airways functioning as a local regulator of bronchomotor tone and possibly serving to override responses to strong, potentially asphyxial bronchoconstrictive stimuli.

Regulation of bronchomotor tone in conscious calves.

The purpose of this study was to investigate the effects of some alpha and beta sympathomimetic and sympatholytic drugs on respiratory impedance in healthy conscious calves. Ten Friesian calves were investigated in this study. The forced oscillation technique was used to measure the resistance (Rrs) and the reactance (Xrs) of the respiratory system at frequencies ranging from 4 to 26 Hz. Isoprenaline (1 microgram/kg i.v.), propranolol (3 micrograms/kg i.v.), noradrenaline (2 micrograms/kg i.v.), xylazine (20 micrograms/kg i.v.) and yohimbine (0.25 mg/kg i.v.) were were administered. Isoprenaline induced a significant decrease of Rrs. An increase of Rrs after administration of propranolol was observed but without any change of the frequency dependence of Rrs. A small increase in the resonant frequency was also recorded. A decrease of Rrs was recorded after yohimbine injection. Noradrenaline and xylazine administration increased the resistances and the resonant frequency and induced a negative frequency dependence of Rrs. These results suggest that (1) the major effects of beta adrenergic drugs are on the central airways, (2) the alpha adrenergic system may play a role on the regulation of bronchomotor tone in calves, (3) the effects of alpha adrenergic drugs are on both central and peripheral airways and (4) the forced oscillation technique allows the differentiation of calibre changes occurring in small and large airways.

Ketanserin, A New Blocking Agent of Serotonin S2-Receptors: Respiratory Functional Effects in Chronic Obstruction of the Airways

The role played by serotonin (5-HT) in the regulation of bronchomotor tone has up to now been a much debated question, although there is good evidence that it induces intense bronchoconstriction after inhalation in asthmatic patients. Serotonin has been found to contract the tracheobronchial smooth muscle of different animals. Some data suggest that tracheobronchial contraction due to serotonin is mediated by its interaction with the S2-receptor. The blockade of this receptor by ketanserin, a serotoninergic antagonist which primarily binds to S2-serotoninergic receptors, produces bronchodilation. The respiratory effects of intravenously administered ketanserin (10 mg) or placebo were compared in a double-blind crossover study in 14 patients with chronic obstruction of the airways. The forced expiratory volume in one second (FEV1) and the instantaneous forced expiratory flow after 50 percent of the forced vital capacity has been exhaled (FEF50%) did not change after placebo, but they increased significantly after administration of ketanserin. The results suggest that in patients with chronic obstructive pulmonary disease, serotonin may play a role in the development of obstruction of the airways, even if the mechanism remains undefined.

Homeostatic regulation of bronchomotor tone by sympathetic activation during bronchoconstriction in normal and asthmatic humans.

It has been assumed previously that the sympathetic nervous system (SNS) serves to antagonize bronchoconstrictor stimuli. To assess the homeostatic regulatory effect elicited by exogenously induced bronchoconstriction, we studied the effect of inhaled methacholine on the SNS response in 12 normal and 9 asthmatic humans. Exogenous SNS response was assessed as change in plasma epinephrine and norepinephrine concentrations from basal levels during inhalation challenge. A 74 +/- 3% decrease in specific airway conductance (SGaw) (p less than 0.001) was induced in normal subjects and a 78 +/- 7% decrease in asthmatics by methacholine challenge (p less than 0.001). Neither plasma epinephrine nor norepinephrine increased significantly from basal concentrations in normal or asthmatic subjects after maximal challenge (p greater than 0.33). To determine if physiologically achievable epinephrine concentrations potentially could modulate bronchoconstriction, the effect of intravenously infused epinephrine was measured in 11 of these subjects. After the highest dose of methacholine, a 15-min intravenous infusion of epinephrine (0.06 micrograms/kg/min) caused an 85 +/- 7% increase in SGaw in normal subjects (p less than 0.02). In asthmatics, a 319 +/- 68% increase in SGaw (p less than 0.002) was observed with similar changes in plasma epinephrine. Plasma epinephrine concentrations after infusion were comparable to those obtained in 4 normal and 1 asthmatic subject undergoing 60-degree, head-up tilt 1 h after volume depletion with intravenously administered furosemide. We conclude that physiologic concentrations of epinephrine can modulate moderately severe bronchoconstriction. However, the SNS does not regulate bronchomotor tone during mild to moderate bronchoconstriction.

Effect of inspiratory flow rate on bronchomotor tone in normal and asthmatic subjects.

The effect of the inspiratory flow rate during deep inspiration on the regulation of bronchomotor tone was studied in nine normal and 22 asthmatic subjects. Changes in bronchial tone were assessed by respiratory resistance measured by an oscillation method. In normal subjects with bronchoconstriction induced by methacholine a rapid deep inspiration reduced respiratory resistance more than a slow deep inspiration. Asthmatic subjects with spontaneous airway narrowing showed an increase in respiratory resistance after deep inspiration that was greater after rapid than after slow deep inspiration. On the other hand, in asthmatics with methacholine induced bronchoconstriction, bronchodilatation occurred after deep inspiration and this was also greater after rapid than after slow deep inspiration. Lignocaine inhalation attenuated both bronchoconstriction and bronchodilatation induced by both slow and rapid deep inspiration. These results suggest that the effects of deep inspiration are mediated at least in part via receptors in the airways. It is suggested that in asthmatic patients with spontaneous bronchoconstriction irritant receptor activity will be increased in proportion to the speed of inspiration. After methacholine induced bronchoconstriction stretch receptor activity is likely to behave in a similar fashion, leading to an opposite effect.

Regulation of bronchomotor tone by lung inflation in asthmatic and nonasthmatic subjects.

We examined the effects of lung inflation on induced airway obstruction in 14 atopic asthmatic and 14 atopic nonasthmatic subjects. Subjects were challenged with aerosols of methacholine (MCh) and pollen antigen (Ag), and the effects of inflation were assessed with partial ad full flow-volume curves and by comparing airway conductance measurements before and after deep inspiration to total lung capacity (TLC). Whereas bronchoconstriction was transiently abolished or reduced with inspiration in nonasthmatics, these effects were absent or diminished in asthmatic subjects. Dissimilarities could not be explained by differences in base-line lung function or degree of obstruction produced. Deep inspiration had a greater effect in reducing airway obstruction produced with MCh than with Ag in nonasthmatics. In addition, atropine pretreatment had no effect on inspiration responses in asthmatics given Ag, suggesting that vagal reflexes were not the cause of an impaired ability to reduce bronchomotor tone by lung inflation. Our findings reveal the existence of an intrinsic means of regulating bronchomotor toe by active changes in lung volume and that such a mechanism is impaired in asthma. We suggest that airway hyperactivity in asthma is perhaps less a reflection of enhanced end-organ responsiveness than a reflection of this impaired capacity.

Thromboxane B 2 — comparative bronchoactivity in experimental systems

Thromboxane B 2 (TxB 2), a major product of prostaglandin endoperoxide metabolism, was examined quantitatively for bronchoactivity in the intact, anesthetized dog and on the isolated guinea pig trachea. In the dog, TxB 2 (0.1 − 30.0 μg/kg i.v.) produced dose-related decreases in airflow rate, tidal volume and dynamic lung compliance, while simultaneously increasing pulmonary airway resistance. These pulmonary changes were qualitatively similar to those observed for PGF 2α, yet were only 0.07-0.11 times as effective. Aerosolized TxB 2 (0.001 − 0.1%) also produced smaller alterations in pulmonary mechanics than did aerosols of PGF 2α. All respiratory changes returned to pre-drug levels within 5–10 min. In the isolated tracheal preparation, TxB 2 (10 6-10 4 M) contracted the strips to a lesser degree than acetylcholine, histamine, PGF 2α, or two PG cyclic ether endoperoxide analogs. TxB 2 appears to be a naturally occurring bronchoactive metabolite (albeit weak) in the bioconversion of arachidonic acid. Since it is produced in substantial amounts in the lungs comparable to the prostaglandins, TxB 2 or its more active immediate precursor, TxB 2, may be involved in regulating bronchomotor tone in the healthy state and/or bronchospasm in the pathological state.

Regulation of bronchomotor tone during anesthesia.

Regulation of bronchomotor tone during anesthesia.