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1
Martin, J. G., A. Opazo-Saez, T. Du, R. Tepper, and D. H. Eidelman. "In vivo airway reactivity: predictive value of morphological estimates of airway smooth muscle." Canadian Journal of Physiology and Pharmacology 70, no. 4 (April 1, 1992): 597–601. http://dx.doi.org/10.1139/y92-076.
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Airway responsiveness to methacholine and other bronchoconstrictors is highly variable within and among species. The aim of the experiments in this report was to evaluate the importance of the quantity of airway smooth muscle as a determinant of intra- and inter-species variability in airway responsiveness. To do this we established concentration–response curves to methacholine in a sample of normal guinea pigs as well as in rat, rabbit, and dog. After challenge we excised the lungs for the quantitation of smooth muscle by morphometry. Animals were anesthetized with pentobarbital and mechanically ventilated using a Harvard ventilator. Aerosols of methacholine were administered in progressively doubling concentrations from 0.0625 to 256 mg/mL for a period of 30 s for each concentration. The maximal response, determined from pulmonary resistance (RL), and the concentration of methacholine required to effect 50% of the maximal RL were determined. After provocation testing the lungs were removed and fixed with 10% Formalin. Midsagittal sections and parahilar sections were stained with hematoxylin–phloxine–saffron for microscopic examination of smooth muscle. The images of all airways in the sections were traced using a camera lucida side-arm attachment and digitized using commercial software. The area of the airway wall occupied by smooth muscle was determined and standardized for airway size by dividing it by the square of the epithelial basement membrane length. The variability in airway smooth muscle in the intraparenchymal airways was significantly greater between than within individual guinea pigs (n = 13). This was not true of extraparenchymal airways. There was a significant relationship between the quantity of airway smooth muscle in the intraparenchymal cartilaginous airways and the EC50 but not the maximal value of resistance (Rmax). In contrast there was a statistically significant positive correlation between Rmax and airway smooth muscle for all species. There was also a significant inverse correlation between EC50 and airway smooth muscle for all species. We conclude that airway smooth muscle appears to be an important determinant of inter-animal differences in sensitivity of guinea pigs to aerosolized methacholine. Smooth muscle also appears to be a determinant of interspecies differences in both sensitivity and maximal responses to methacholine.Key words: airways responsiveness, mechanical determinants, limited bronchoconstriction, methacholine, morphometry.
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Dowell, Maria L., Tera L. Lavoie, Julian Solway, and Ramaswamy Krishnan. "Airway smooth muscle." Current Opinion in Pulmonary Medicine 20, no. 1 (January 2014): 66–72. http://dx.doi.org/10.1097/mcp.0000000000000011.
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Mitzner, Wayne. "Airway Smooth Muscle." American Journal of Respiratory and Critical Care Medicine 169, no. 7 (April 2004): 787–90. http://dx.doi.org/10.1164/rccm.200312-1636pp.
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Rodger, I. W. "Airway smooth muscle." British Medical Bulletin 48, no. 1 (1992): 97–107. http://dx.doi.org/10.1093/oxfordjournals.bmb.a072545.
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Stephens, N. L. "Airway Smooth Muscle." Lung 179, no. 6 (December 1, 2001): 333–73. http://dx.doi.org/10.1007/s004080000073.
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Gallos, George, Elizabeth Townsend, Peter Yim, Laszlo Virag, Yi Zhang, Dingbang Xu, Matthew Bacchetta, and Charles W. Emala. "Airway epithelium is a predominant source of endogenous airway GABA and contributes to relaxation of airway smooth muscle tone." American Journal of Physiology-Lung Cellular and Molecular Physiology 304, no. 3 (February 1, 2013): L191—L197. http://dx.doi.org/10.1152/ajplung.00274.2012.
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Chronic obstructive pulmonary disease and asthma are characterized by hyperreactive airway responses that predispose patients to episodes of acute airway constriction. Recent studies suggest a complex paradigm of GABAergic signaling in airways that involves GABA-mediated relaxation of airway smooth muscle. However, the cellular source of airway GABA and mechanisms regulating its release remain unknown. We questioned whether epithelium is a major source of GABA in the airway and whether the absence of epithelium-derived GABA contributes to greater airway smooth muscle force. Messenger RNA encoding glutamic acid decarboxylase (GAD) 65/67 was quantitatively measured in human airway epithelium and smooth muscle. HPLC quantified GABA levels in guinea pig tracheal ring segments under basal or stimulated conditions with or without epithelium. The role of endogenous GABA in the maintenance of an acetylcholine contraction in human airway and guinea pig airway smooth muscle was assessed in organ baths. A 37.5-fold greater amount of mRNA encoding GAD 67 was detected in human epithelium vs. airway smooth muscle cells. HPLC confirmed that guinea pig airways with intact epithelium have a higher constitutive elution of GABA under basal or KCl-depolarized conditions compared with epithelium-denuded airway rings. Inhibition of GABA transporters significantly suppressed KCl-mediated release of GABA from epithelium-intact airways, but tetrodotoxin was without effect. The presence of intact epithelium had a significant GABAergic-mediated prorelaxant effect on the maintenance of contractile tone. Airway epithelium is a predominant cellular source of endogenous GABA in the airway and contributes significant prorelaxant GABA effects on airway smooth muscle force.
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Robinson, Philip, Mitsushi Okazawa, Tony Bai, and Peter Paré. "In vivo loads on airway smooth muscle: the role of noncontractile airway structures." Canadian Journal of Physiology and Pharmacology 70, no. 4 (April 1, 1992): 602–6. http://dx.doi.org/10.1139/y92-077.
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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.
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Jiang, He, Kang Rao, Xueliang Liu, Andrew J. Halayko, Gang Liu, and Newman L. Stephens. "Early changes in airway smooth muscle hyperresponsiveness." Canadian Journal of Physiology and Pharmacology 72, no. 11 (November 1, 1994): 1440–47. http://dx.doi.org/10.1139/y94-208.
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To study asthmatic airway smooth muscle we developed a canine model of ragweed pollen sensitized, airway hyperresponsiveness because of the difficulties in obtaining human tissue. Tracheal and bronchial smooth muscles from sensitized dogs were shown to possess greater ability to shorten and higher maximum shortening velocity (Vo), both of which contribute to the excessive narrowing of airways typical of human asthma. However, maximum force production remained normal, demonstrating the dissociation between the behaviour of shortening and force. Because we found no evidence of inflammation, hypertrophy, or hyperplasia in the sensitized airway smooth muscles, we felt this is a model of early disease and should provide insight into early and perhaps primary pathogenetic mechanisms. Vo is known to be determined by actornyosin ATPase, which in smooth muscle is activated via phosphorylation of the 20-kDa myosin light chain (MLC20) by myosin light chain kinase (MLCK). Therefore, ATPase activity, MLC20 phosphorylation, and MLCK were investigated. Sensitized tracheal and bronchial smooth muscles showed significantly higher ATPase activity, and a higher level of MLC20 phosphorylation, resulting from increased MLCK activity, a consequence of the measured increase in total quantity of MLCK rather than in specific activity. Since MLCK is activated by binding with Ca2+–calmodulin complex, intracellular Ca2+ concentration and calmodulin activity were also assessed, but no difference was found between sensitized and control animals. Our study suggests that increased MLCK quantity may be the cause of airway hyperresponsiveness found in sensitized animals, and future investigation should be focused on depicting the reason for the elevated MLCK.Key words: airway hyperresponsiveness, smooth muscle, biophysics, biochemistry, early asthmatic changes.
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Halayko, Andrew J., and Newman L. Stephens. "Potential role for phenotypic modulation of bronchial smooth muscle ceils in chronic asthma." Canadian Journal of Physiology and Pharmacology 72, no. 11 (November 1, 1994): 1448–57. http://dx.doi.org/10.1139/y94-209.
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Asthma is considered to be a chronic inflammatory disease of the airways and is highlighted by excessive airway narrowing in response to various stimuli. Subepithelial fibrosis and increased airway smooth muscle mass are characteristic pathological features of the disease. Airway remodelling in asthma involves cellular hyperplasia and hypertrophy of bronchial myocytes. Smooth muscle cells from a variety of tissues have been shown to be multifunctional mesenchymal cells capable of expressing considerable phenotypic plasticity in vivo in response to injury and pathological stimuli. The growth response of vascular smooth muscle cells following arterial injury has been fairly well characterized, and it appears many of the chemical mediators responsible are common to the inflamed bronchi seen in asthmatics. Specific studies regarding the effects of phenotypic modulation of airway smooth muscle and the potential contribution of this phenomenon to the pathogenesis of chronic asthma have not been carried out. Limited evidence, some indirect, suggests that contractile properties of smooth muscle from inflamed tissues are altered; if this is the case in asthma, then considerations of the effects of airway smooth muscle hypertrophy should be broadened beyond that of only contributing to bronchial hyperresponsiveness via an increase in bronchial wall thickness. Recruitment and modulation of smooth muscle cells to functionally different phenotypes, which contribute to fibrosis by secreting extracellular matrix materials and promote cellular hyperplasia by producing growth factors, are known to occur in atherogenic blood vessels; and evidence suggests that airway smooth muscle cells might play a similar role in asthma. We report the identification of markers of differentiation for airway smooth muscle cells. These markers should be useful tools in the elucidation of phenotypic heterogeneity of smooth muscle in asthmatic airways and, thereby, allow for the definition of a clearer role for bronchial smooth muscle cells in the pathogenesis of chronic asthma.Key words: airway smooth muscle cells, asthma, phenotype, pathogenesis, proliferation.
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Pascoe, C. D., L. Wang, H. T. Syyong, and P. D. Paré. "A Brief History of Airway Smooth Muscle’s Role in Airway Hyperresponsiveness." Journal of Allergy 2012 (October 18, 2012): 1–8. http://dx.doi.org/10.1155/2012/768982.
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A link between airway smooth muscle (ASM) and airway hyperresponsiveness (AHR) in asthma was first postulated in the midnineteenth century, and the suspected link has garnered ever increasing interest over the years. AHR is characterized by excessive narrowing of airways in response to nonspecific stimuli, and it is the ASM that drives this narrowing. The stimuli that can be used to demonstrate AHR vary widely, as do the potential mechanisms by which phenotypic changes in ASM or nonmuscle factors can contribute to AHR. In this paper, we review the history of research on airway smooth muscle’s role in airway hyperresponsiveness. This research has ranged from analyzing the quantity of ASM in the airways to testing for alterations in the plastic behavior of smooth muscle, which distinguishes it from skeletal and cardiac muscles. This long history of research and the continued interest in this topic mean that the precise role of ASM in airway responsiveness remains elusive, which makes it a pertinent topic for this collection of articles.
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Noble, P. B., D. J. Turner, and H. W. Mitchell. "Relationship of airway narrowing, compliance, and cartilage in isolated bronchial segments." Journal of Applied Physiology 92, no. 3 (March 1, 2002): 1119–24. http://dx.doi.org/10.1152/japplphysiol.00662.2001.
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Structural components of the airway wall may act to load airway smooth muscle and restrict airway narrowing. In this study, the effect of load on airway narrowing was investigated in pig isolated bronchial segments. In some bronchi, pieces of cartilage were removed by careful dissection. Airway narrowing was produced by maximum electrical field stimulation. An endoscope was used to record lumen narrowing. The compliance of the bronchial segments was determined from the cross-sectional area of the lumen and the transmural pressure. Airway narrowing and the velocity of airway narrowing were increased in cartilage-removed airways compared with intact control bronchi. Morphometric assessment of smooth muscle length showed greater muscle shortening to acetylcholine in cartilage-removed airways than in controls. Airway narrowing was positively correlated with airway compliance. Compliance and area of cartilage were negatively correlated. These results show that airway narrowing is increased in compliant airways and that cartilage significantly loads airway smooth muscle in whole bronchi.
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Tran, Thai, and Andrew J. Halayko. "Extracellular matrix and airway smooth muscle interactions: a target for modulating airway wall remodelling and hyperresponsiveness?This article is one of a selection of papers published in the Special Issue on Recent Advances in Asthma Research." Canadian Journal of Physiology and Pharmacology 85, no. 7 (July 2007): 666–71. http://dx.doi.org/10.1139/y07-050.
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The airway smooth muscle from asthmatic airways produces increased amounts and an altered composition of extracellular matrix proteins. The extracellular matrix can in turn influence the phenotype and function of airway smooth muscle cells, affecting the biochemical, geometric, and mechanical properties of the airway wall. This review provides a brief overview of the current understanding of the biology associated with airway smooth muscle interactions with the extracellular matrix. We present future directions needed for the study of cellular and molecular mechanisms that determine the outcomes of extracellular matrix – airway smooth muscle interactions, and discuss their possible importance as determinants of airway function in asthma.
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Tran, Mai-Uyen T., Alison J. Weir, Michelle V. Fanucchi, April E. Murphy, Laura S. Van Winkle, Michael J. Evans, Suzette M. Smiley-Jewell, et al. "Smooth muscle development during postnatal growth of distal bronchioles in infant rhesus monkeys." Journal of Applied Physiology 97, no. 6 (December 2004): 2364–71. http://dx.doi.org/10.1152/japplphysiol.00476.2004.
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Development of smooth muscle in conducting airways begins early in fetal life. Whereas the pattern and regulation of smooth muscle differentiation are well-defined, the impact of airway growth on the process is not. To evaluate the transformations in organization during postnatal growth, smooth muscle bundle organization (size, abundance, and orientation) was mapped in five generations of distal airways of infant rhesus monkeys (5 days and 1, 2, 3, and 6 mo old). On the basis of direct measurement of the bronchiole proximal to the terminal bronchiole, length increased by 2-fold, diameter by 1.35-fold, and surface area by 2.8-fold between 5 days and 6 mo of age. Smooth muscle bundle size was greater in proximal bronchioles than in respiratory bronchioles and did not change with age. However, relative bundle size decreased in proportion to airway size as the airways grew. Relative bundle abundance was constant regardless of airway generation or age. The distribution of smooth muscle bundle orientation changed with age in each airway generation, and there were significant changes in the terminal and respiratory bronchioles. We conclude that smooth muscle undergoes marked organizational changes as airways grow during postnatal development.
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Gerthoffer, W. T. "Regulation of the contractile element of airway smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 261, no. 2 (August 1, 1991): L15—L28. http://dx.doi.org/10.1152/ajplung.1991.261.2.l15.
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Smooth muscle of the mammalian airways controls airway diameter and resistance to airflow. Smooth muscle tone is in turn controlled by a variety of external signals that are transduced to useful work by contractile proteins. The protein components of the contractile element of airway smooth muscle are similar to those found in other smooth muscles and include actin, myosin, tropomyosin, caldesmon, and calponin. There has been significant recent progress in studies of contractile system regulation of airway smooth muscle. Regulation of myosin light chain kinase, identification of the sites phosphorylated on the regulatory myosin light chains, and the effect of myosin phosphorylation on stress development and crossbridge cycling rates have all been studied in some detail. We infer from these studies that besides myosin phosphorylation there is an important role for a thin filament Ca(2+)-dependent regulatory mechanism. The potentially important thin filament proteins caldesmon and calponin are present in tracheal smooth muscle and may be phosphorylated during contraction. The use of intracellular Ca2+ indicators to estimate changes in intracellular Ca2+ ([Ca2+]i) and the development of several skinned fiber preparations have broadened the scope of physiological studies with airway smooth muscle and have suggested that the contractile element sensitivity to Ca2+ is not fixed but might be modulated by undefined messengers or excitation-contraction pathways. This adds an additional challenge to the continuing effort to define the messengers and regulatory proteins that couple activation of membrane receptors to the contractile element in airway smooth muscle.
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Turner, Debra J., Peter B. Noble, Matthew P. Lucas, and Howard W. Mitchell. "Decreased airway narrowing and smooth muscle contraction in hyperresponsive pigs." Journal of Applied Physiology 93, no. 4 (October 1, 2002): 1296–300. http://dx.doi.org/10.1152/japplphysiol.00150.2002.
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Increased smooth muscle contractility or reduced smooth muscle mechanical loads could account for the excessive airway narrowing and hyperresponsiveness seen in asthma. These mechanisms were investigated by using an allergen-induced porcine model of airway hyperresponsiveness. Airway narrowing to electric field stimulation was measured in isolated bronchial segments, over a range of transmural pressures (0–20 cmH2O). Contractile responses to ACh were measured in bronchial segments and in isolated tracheal smooth muscle strips isolated from control and test (ovalbumin sensitized and challenged) pigs. Test airways narrowed less than controls ( P < 0.0001). Test pigs showed reduced contractility to ACh, both in isolated bronchi ( P < 0.01) and smooth muscle strips ( P < 0.01). Thus isolated airways from pigs exhibiting airway hyperresponsiveness in vivo are hyporesponsive in vitro. The decreased narrowing in bronchi from hyperresponsive pigs may be related to decreased smooth muscle contractility. These data suggest that mechanisms external to the airway wall may be important to the hyperresponsive nature of sensitized lungs.
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Finkelman, Fred D., Charles Perkins, George Smulian, Lucy Gildea, Tatyana Orekov, Crystal Potter, Frank Brombacher, and Marsha Wills-Karp. "Selective stimulation of IL-4 receptor on smooth muscle induces airway hyperresponsiveness in mice (79.9)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 79.9. http://dx.doi.org/10.4049/jimmunol.182.supp.79.9.
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Abstract Hyperresponsiveness to cholinergic stimulation of increased airway resistance is a defining characteristic of asthma. Both IL-4 and IL-13 activate Stat6 via IL-4Rα to induce airway hyperresponsiveness (AHR) in mouse models of asthma and increase mouse and human smooth muscle contractility in vitro. However, the relatively small size of mouse vs. human airways, differences in airway smooth muscle cell distribution between mouse and human, and observations that selective IL-13 stimulation of Stat6 in airway epithelium is sufficient to induce AHR in mice have raised questions about the importance of direct IL-4/IL-13 effects on smooth muscle in murine models of allergic airway disease and whether these models are appropriate for studying AHR in human asthma. To determine whether direct effects of IL-4/IL-13 on smooth muscle contribute to murine allergic airway disease, we produced mice that express IL-4Rα only on smooth muscle and evaluated the effects of intratracheal IL-4, IL-13 and allergen on their airways. We demonstrate that IL-4 and IL-13 induce AHR in these mice, without stimulating goblet cell hyperplasia or airway eosinophilia. Similar results were observed following airway inoculation of these mice with a potent allergen. Thus, allergen-stimulated IL-4/IL-13 can induce AHR in mice through direct effects on airway smooth muscle.
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Okazawa, M., S. Vedal, L. Verburgt, R. K. Lambert, and P. D. Pare. "Determinants of airway smooth muscle shortening in excised canine lobes." Journal of Applied Physiology 78, no. 2 (February 1, 1995): 608–14. http://dx.doi.org/10.1152/jappl.1995.78.2.608.
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There is marked heterogeneity of airway narrowing in intraparenchymal airways in response to bronchoconstricting stimuli. We hypothesized that this heterogeneity results from variations in the structure of the airway wall. Freshly excised dog lung lobes were inflated to transpulmonary pressures (PL) of between 5 and 15 cmH2O, and an aerosol containing a high concentration of carbachol was administered. The lobes were fixed and processed for light-microscopic examination and morphometric analysis of membranous airway dimensions. The relationships of smooth muscle shortening to PL and airway dimensions were analyzed using multiple linear regression. The results show that airway smooth muscle shortening was greater at lower PL and in airways with larger internal perimeter and a greater number of folds per internal perimeter and that it was less in airways with greater inner wall area. We conclude that the magnitude and variability of airway smooth muscle shortening and airway narrowing in response to maximal constricting stimuli are influenced by mechanical factors related to airway wall geometry.
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Lei, M., H. Ghezzo, M. F. Chen, and D. H. Eidelman. "Airway smooth muscle orientation in intraparenchymal airways." Journal of Applied Physiology 82, no. 1 (January 1, 1997): 70–77. http://dx.doi.org/10.1152/jappl.1997.82.1.70.
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Lei, M., H. Ghezzo, M. F. Chen, and D. H. Eidelman.Airway smooth muscle orientation in intraparenchymal airways. J. Appl. Physiol. 82(1): 70–77, 1997.—Airway smooth muscle (ASM) shortening is the central event leading to bronchoconstriction. The degree to which airway narrowing occurs as a consequence of shortening is a function of both the mechanical properties of the airway wall as well as the orientation of the muscle fibers. Although the latter is theoretically important, it has not been systematically measured to date. The purpose of this study was to determine the angle of orientation of ASM (θ) in normal lungs by using a morphometric approach. We analyzed the airway tree of the left lower lobes of four cats and one human. All material was fixed with 10% buffered Formalin at a pressure of 25 cmH2O for 48 h. The fixed material was dissected along the airway tree to permit isolation of generations 4–18 in the cats and generations 5–22 in the human specimen. Each airway generation was individually embedded in paraffin. Five-micrometer-thick serial sections were cut parallel to the airway long axis and stained with hematoxylin-phloxine-saffron. Each block yielded three to five sections containing ASM. To determine θ, we measured the orientation of ASM nuclei relative to the transverse axis of the airway by using a digitizing tablet and a light microscope (×250) equipped with a drawing tube attachment. Inspection of the sections revealed extensive ASM crisscrossing without a homogeneous orientation. The θ was clustered between −20° and 20° in all airway generations and did not vary much between generations in any of the cats or in the human specimen. When θ was expressed without regard to sign, the mean values were 13.2° in the cats and 13.1° in the human. This magnitude of obliquity is not likely to result in physiologically important changes in airway length during bronchoconstriction.
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Saez, Anabelle M. Opazo, R. Robert Schellenberg, Mara S. Ludwig, Richard A. Meiss, and Peter D. Paré. "Tissue elastance influences airway smooth muscle shortening: comparison of mechanical properties among different species." Canadian Journal of Physiology and Pharmacology 80, no. 9 (September 1, 2002): 865–71. http://dx.doi.org/10.1139/y02-112.
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We have observed striking differences in the mechanical properties of airway smooth muscle preparations among different species. In this study, we provide a novel analysis on the influence of tissue elastance on smooth muscle shortening using previously published data from our laboratory. We have found that isolated human airways exhibit substantial passive tension in contrast to airways from the dog and pig, which exhibit little passive tension (<5% of maximal active force versus ~60% for human bronchi). In the dog and pig, airway preparations shorten up to 70% from Lmax (the length at which maximal active force occurs), whereas human airways shorten by only ~12% from Lmax. Isolated airways from the rabbit exhibit relatively low passive tension (~22% Fmax) and shorten by 60% from Lmax. Morphologic evaluation of airway cross sections revealed that 25-35% of the airway wall is muscle in canine, porcine, and rabbit airways in contrast to ~9% in human airway preparations. We postulate that the large passive tension needed to stretch the muscle to Lmax reflects the high connective tissue content surrounding the smooth muscle, which limits shortening during smooth muscle contraction by imposing an elastic load, as well as by causing radial constraint.Key words: isometric force, isotonic shortening, elastance.
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Ma, X., W. Li, and N. L. Stephens. "Detection of two clusters of mechanical properties of smooth muscle along the airway tree." Journal of Applied Physiology 80, no. 3 (March 1, 1996): 857–61. http://dx.doi.org/10.1152/jappl.1996.80.3.857.
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Heterogeneity of function of airway smooth muscle along the airways may be of great importance in regulating regional ventilation and in the pathogenesis of asthma. To investigate the distribution of mechanical properties of airway smooth muscle along the airway, muscle strips free of cartilage and epithelium from the trachea down to bronchial generation 6 were studied by employing electrical field stimulation. Results showed that smooth muscle mechanical performance decreased progressively down the airway tree. Cluster analysis further indicated that smooth muscle from these airways could be divided into two groups: 1) an extrapulmonary group, which contains muscle from the trachea and bronchial generations 1 and 2 and is characterized by higher maximum shortening capacity and zero-load velocity of shortening (V0) in early shortening, the expected decrease of V0 values (the so-called latch phase) in the later phase of shortening, and lower sensitivity to stimulation; and 2) an intrapulmonary group, which contains bronchi from generations 3-6 and has a lower maximum shortening capacity and V0 in early shortening but higher sensitivity to stimulation. The relatively lower mechanical performance of intrapulmonary bronchial smooth muscle may represent a safety device that prevents excessive smooth muscle shortening in vivo.
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Erle, David J., and Dean Sheppard. "The cell biology of asthma." Journal of Cell Biology 205, no. 5 (June 9, 2014): 621–31. http://dx.doi.org/10.1083/jcb.201401050.
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The clinical manifestations of asthma are caused by obstruction of the conducting airways of the lung. Two airway cell types are critical for asthma pathogenesis: epithelial cells and smooth muscle cells. Airway epithelial cells, which are the first line of defense against inhaled pathogens and particles, initiate airway inflammation and produce mucus, an important contributor to airway obstruction. The other main cause of airway obstruction is contraction of airway smooth muscle. Complementary experimental approaches involving cultured cells, animal models, and human clinical studies have provided many insights into diverse mechanisms that contribute to airway epithelial and smooth muscle cell pathology in this complex disease.
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Knox, A. J., and A. E. Tattersfield. "Airway smooth muscle relaxation." Thorax 50, no. 8 (August 1, 1995): 894–901. http://dx.doi.org/10.1136/thx.50.8.894.
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Bates, J. H., and J. G. Martin. "A theoretical study of the effect of airway smooth muscle orientation on bronchoconstriction." Journal of Applied Physiology 69, no. 3 (September 1, 1990): 995–1001. http://dx.doi.org/10.1152/jappl.1990.69.3.995.
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If airway smooth muscle shortened in vivo to the extent that it does in vitro, then maximal bronchoconstriction would result in complete closure of virtually all airways. The fact that this does not happen indicates the existence of inhibitory mechanisms preventing maximal muscle shortening. There are many factors potentially limiting shortening in vivo. In this study we investigated one of these factors, the orientation of the smooth muscle around the airway wall. The airway was modeled as a cylinder of given wall thickness around which the muscle was wound as a spiral. The longitudinal and circumferential elasticities of the airway were embodied in a 2 x 2 matrix of elastic coefficients. We investigated smooth muscle shortening under three conditions: 1) a longitudinally stiff airway, 2) a circumferentially stiff airway, and 3) a longitudinally and circumferentially compressible airway. In case 1, for a given degree of smooth muscle shortening, airway resistance increased markedly with increasing pitch of the smooth muscle spiral. On the other hand, the muscle tension required to elicit a given change in resistance also increased markedly with pitch. In case 2, the effect with increasing pitch was reversed. In case 3, resistance first increased and then decreased as spiral pitch increased. Similarly, the muscle tension required to elicit a given change in resistance first increased and then decreased with pitch. These results suggest that the orientation of the smooth muscle about the airway may be very important in determining airway responsiveness.
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BAI, Tony R., and Darryl A. KNIGHT. "Structural changes in the airways in asthma: observations and consequences." Clinical Science 108, no. 6 (May 24, 2005): 463–77. http://dx.doi.org/10.1042/cs20040342.
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Structural changes reported in the airways of asthmatics include epithelial fragility, goblet cell hyperplasia, enlarged submucosal mucus glands, angiogenesis, increased matrix deposition in the airway wall, increased airway smooth muscle mass, wall thickening and abnormalities in elastin. Genetic influences, as well as fetal and early life exposures, may contribute to structural changes such as subepithelial fibrosis from an early age. Other structural alterations are related to duration of disease and/or long-term uncontrolled inflammation. The increase in smooth muscle mass in both large and small airways probably occurs via multiple mechanisms, and there are probably changes in the phenotype of smooth muscle cells, some showing enhanced synthetic capacity, others enhanced proliferation or contractility. Fixed airflow limitation is probably due to remodelling, whereas the importance of structural changes to the phenomenon of airways hyperresponsiveness may be dependent on the specific clinical phenotype of asthma evaluated. Reduced compliance of the airway wall secondary to enhanced matrix deposition may protect against airway narrowing. Conversely, in severe asthma, disruption of alveolar attachments and adventitial thickening may augment airway narrowing. The encroachment upon luminal area by submucosal thickening may be disadvantageous by increasing the risk of airway closure in the presence of the intraluminal cellular and mucus exudate associated with asthma exacerbations. Structural changes may increase airway narrowing by alteration of smooth muscle dynamics through limitation of the ability of the smooth muscle to periodically lengthen.
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Canning, Brendan J. "Reflex regulation of airway smooth muscle tone." Journal of Applied Physiology 101, no. 3 (September 2006): 971–85. http://dx.doi.org/10.1152/japplphysiol.00313.2006.
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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.
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Sparrow, M. P., P. K. McFawn, T. I. Omari, and H. W. Mitchell. "Activation of smooth muscle in the airway wall, force production, and airway narrowing." Canadian Journal of Physiology and Pharmacology 70, no. 4 (April 1, 1992): 607–14. http://dx.doi.org/10.1139/y92-078.
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Airway narrowing depends on smooth muscle force production and muscle shortening, but the structural and geometric properties exhibited by individual generations of the bronchial tree largely determine the extent and characteristics of airway narrowing. Properties of major importance include the nature and integrity of the epithelium, the structural and mechanical properties of the airway wall, as well as airway diameter. The influence of these properties on airway narrowing measured as flow or flow resistance in large and small diameter segments of airways from pig lung is described using a novel preparation, the perfused bronchial segment.Key words: airway narrowing, bronchi, smooth muscle, epithelium.
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Saunders, Ruth, Himanshu Kaul, Rachid Berair, Sherif Gonem, Amisha Singapuri, Amanda J. Sutcliffe, Latifa Chachi, et al. "DP2 antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment." Science Translational Medicine 11, no. 479 (February 13, 2019): eaao6451. http://dx.doi.org/10.1126/scitranslmed.aao6451.
Full textAbstract:
Increased airway smooth muscle mass, a feature of airway remodeling in asthma, is the strongest predictor of airflow limitation and contributes to asthma-associated morbidity and mortality. No current drug therapy for asthma is known to affect airway smooth muscle mass. Although there is increasing evidence that prostaglandin D2 type 2 receptor (DP2) is expressed in airway structural and inflammatory cells, few studies have addressed the expression and function of DP2 in airway smooth muscle cells. We report that the DP2 antagonist fevipiprant reduced airway smooth muscle mass in bronchial biopsies from patients with asthma who had participated in a previous randomized placebo-controlled trial. We developed a computational model to capture airway remodeling. Our model predicted that a reduction in airway eosinophilia alone was insufficient to explain the clinically observed decrease in airway smooth muscle mass without a concomitant reduction in the recruitment of airway smooth muscle cells or their precursors to airway smooth muscle bundles that comprise the airway smooth muscle layer. We experimentally confirmed that airway smooth muscle migration could be inhibited in vitro using DP2-specific antagonists in an airway smooth muscle cell culture model. Our analyses suggest that fevipiprant, through antagonism of DP2, reduced airway smooth muscle mass in patients with asthma by decreasing airway eosinophilia in concert with reduced recruitment of myofibroblasts and fibrocytes to the airway smooth muscle bundle. Fevipiprant may thus represent a potential therapy to ameliorate airway remodeling in asthma.
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Brown, Robert H., and Wayne Mitzner. "Airway closure with high PEEP in vivo." Journal of Applied Physiology 89, no. 3 (September 1, 2000): 956–60. http://dx.doi.org/10.1152/jappl.2000.89.3.956.
Full textAbstract:
When airway smooth muscle is contracted in vitro, the airway lumen continues to narrow with increasing concentrations of agonist until complete airway closure occurs. Although there remains some controversy regarding whether airways can close in vivo, recent work has clearly demonstrated that, if the airway is sufficiently stimulated with contractile agonists, complete closure of even large cartilaginous conducting airways can readily occur with the lung at functional residual capacity (Brown RH and Mitzner W. J Appl Physiol 85: 2012–2017, 1998). This result suggests that the tethering of airways in situ by parenchymal attachments is small at functional residual capacity. However, at lung volumes above functional residual capacity, the outward tethering of airways should increase, because both the parenchymal shear modulus and tethering forces increase in proportion to the transpulmonary pressure. In the present study, we tested whether we could prevent airway closure in vivo by increasing lung volume with positive end-expiratory pressure (PEEP). Airway smooth muscle was stimulated with increasing methacholine doses delivered directly to airway smooth muscle at three levels of PEEP (0, 6, and 10 cmH2O). Our results show that increased lung volume shifted the airway methacholine dose-response curve to the right, but, in many airways in most animals, airway closure still occurred even at the highest levels of PEEP.
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Coburn, R. F., and C. B. Baron. "Coupling mechanisms in airway smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 258, no. 4 (April 1, 1990): L119—L133. http://dx.doi.org/10.1152/ajplung.1990.258.4.l119.
Full textAbstract:
This review documents available information about coupling mechanisms involved in airway smooth muscle force development and maintenance and relaxation of force. Basic concepts, obtained from experiments performed on many different mammalian cell types, are in place regarding coupling between surface membrane receptors and cell function; these concepts are considered as a framework for understanding coupling between receptors and contractile proteins in smooth muscles and in airway smooth muscles. We have divided various components of coupling mechanisms into those dependent on changes in the surface membrane potential (electromechanical coupling) and those independent of the surface membrane potential (pharmacomechanical coupling). We have, to some degree, emphasized modulation of coupling mechanisms by intrasurface membrane microprocessing or by second messengers. A challenge for the future is to obtain a better understanding of how coupling mechanisms are altered or modulated during different phases of contractions evoked by a single agonist and under conditions of multiple agonist exposure to airway smooth muscle cells.
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Okazawa, M., T. R. Bai, B. R. Wiggs, and P. D. Pare. "Airway smooth muscle shortening in excised canine lung lobes." Journal of Applied Physiology 74, no. 4 (April 1, 1993): 1613–21. http://dx.doi.org/10.1152/jappl.1993.74.4.1613.
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To estimate the importance of lung parenchymal airway interdependence in attenuating airway narrowing, airway smooth muscle shortening in response to nebulized carbachol was measured in excised canine lung lobes and compared with the calculated load applied by lung elastic recoil. Pulmonary resistance of matched right and left upper lobes of five dogs was measured in a pressure-compensated volume plethysmograph by forced oscillation (6 Hz) before and after administration of an aerosol of carbachol (250 mg/ml) or saline. Matched lobes were studied at transpulmonary pressures (PL) of 5, 7, 10, 12, and 15 cmH2O. The lungs were then fixed at that PL by pulmonary arterial perfusion with formaldehyde, and cross sections of multiple airways from each lobe (n = 275) were examined by use of morphometric techniques to measure luminal area and smooth muscle length. By use of the saline lobe as a control, percentage of muscle shortening and decrease in airway lumen area caused by carbachol could be calculated. Passive and active smooth muscle stresses in each airway were calculated from PL and the calculated change in peribronchial pressure for a given change in airway diameter. The increase in pulmonary resistance and average smooth muscle shortening after administration of carbachol was greater in lobes held at lower PL. There was marked variation in narrowing between airways within a lobe: smooth muscle shortening ranged between 0 and 65% but averaged < 45% at all levels of PL.(ABSTRACT TRUNCATED AT 250 WORDS)
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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." Journal of Applied Physiology 82, no. 2 (February 1, 1997): 491–99. http://dx.doi.org/10.1152/jappl.1997.82.2.491.
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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.
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Mazzone, Stuart B., Lina H. K. Lim, Elizabeth M. Wagner, Nanako Mori, and Brendan J. Canning. "Sympathetic nerve-dependent regulation of mucosal vascular tone modifies airway smooth muscle reactivity." Journal of Applied Physiology 109, no. 5 (November 2010): 1292–300. http://dx.doi.org/10.1152/japplphysiol.00632.2010.
Full textAbstract:
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.
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Chernyavsky, Igor L., Richard J. Russell, Ruth M. Saunders, Gavin E. Morris, Rachid Berair, Amisha Singapuri, Latifa Chachi, et al. "In vitro, in silico and in vivo study challenges the impact of bronchial thermoplasty on acute airway smooth muscle mass loss." European Respiratory Journal 51, no. 5 (April 26, 2018): 1701680. http://dx.doi.org/10.1183/13993003.01680-2017.
Full textAbstract:
Bronchial thermoplasty is a treatment for asthma. It is currently unclear whether its histopathological impact is sufficiently explained by the proportion of airway wall that is exposed to temperatures necessary to affect cell survival.Airway smooth muscle and bronchial epithelial cells were exposed to media (37–70°C) for 10 s to mimic thermoplasty. In silico we developed a mathematical model of airway heat distribution post-thermoplasty. In vivo we determined airway smooth muscle mass and epithelial integrity pre- and post-thermoplasty in 14 patients with severe asthma.In vitro airway smooth muscle and epithelial cell number decreased significantly following the addition of media heated to ≥65°C. In silico simulations showed a heterogeneous heat distribution that was amplified in larger airways, with <10% of the airway wall heated to >60°C in airways with an inner radius of ∼4 mm. In vivo at 6 weeks post-thermoplasty, there was an improvement in asthma control (measured via Asthma Control Questionnaire-6; mean difference 0.7, 95% CI 0.1–1.3; p=0.03), airway smooth muscle mass decreased (absolute median reduction 5%, interquartile range (IQR) 0–10; p=0.03) and epithelial integrity increased (14%, IQR 6–29; p=0.007). Neither of the latter two outcomes was related to improved asthma control.Integrated in vitro and in silico modelling suggest that the reduction in airway smooth muscle post-thermoplasty cannot be fully explained by acute heating, and nor did this reduction confer a greater improvement in asthma control.
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Miki, Haruka, William B. Kiosses, Rana Herro, and Michael Croft. "TNFSF14 (LIGHT) Induces Airway Smooth Muscle Contraction." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 65.6. http://dx.doi.org/10.4049/jimmunol.204.supp.65.6.
Full textAbstract:
Abstract Asthma is a chronic inflammatory disorder characterized by reversible airway obstruction and airway hyperresponsiveness (AHR). The precise mechanism responsible for AHR is not known but it may involve excess mucus production and alterations in airway smooth muscle cell (SMC) activity. SMC from asthmatic patients are thought to generate more force and contract to a greater extent to allergens or certain inflammatory stimuli, but which inflammatory stimuli in asthmatics drive contraction is still not clear. Previously, we showed that the tumor necrosis factor superfamily member LIGHT (TNFSF14) promotes airway remodeling and AHR in mouse models of chronic asthma, despite having little effect on airway eosinophilia. Exogenous administration of rLIGHT to the mouse airways also induced smooth muscle hyperplasia. We found that LTβR and HVEM, the receptors for LIGHT, are expressed on both human and mouse SMC from the lungs, with LTbR primarily expressed on human cells, suggesting a direct effect of this T cell-derived cytokine. From studies in vitro with primary human SMC, we found that rLIGHT administration induced contraction of SMC in collagen-gels in 3D structures, and migration of SMC in monolayers. rLIGHT induced both actin polymerization and phosphorylation of myosin light chain which leads to actomyosin formation to induce contraction. rLIGHT promoted both canonical and non-canonical NF-kB in airway SMC, and these signals activated the small GTPase Rac1 and P21-Activated Kinase 1 (PAK1) which are involved in actin rearrangement and myosin light chain kinase activity. These results reveal direct evidence that LIGHT can drive SMC contraction and may directly regulate airway hyperresponsiveness relevant to asthma pathogenesis.
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Lauzon, Anne-Marie, and James G. Martin. "Airway hyperresponsiveness; smooth muscle as the principal actor." F1000Research 5 (March 9, 2016): 306. http://dx.doi.org/10.12688/f1000research.7422.1.
Full textAbstract:
Airway hyperresponsiveness (AHR) is a defining characteristic of asthma that refers to the capacity of the airways to undergo exaggerated narrowing in response to stimuli that do not result in comparable degrees of airway narrowing in healthy subjects. Airway smooth muscle (ASM) contraction mediates airway narrowing, but it remains uncertain as to whether the smooth muscle is intrinsically altered in asthmatic subjects or is responding abnormally as a result of the milieu in which it sits. ASM in the trachea or major bronchi does not differ in its contractile characteristics in asthmatics, but the more pertinent peripheral airways await complete exploration. The mass of ASM is increased in many but not all asthmatics and therefore cannot be a unifying hypothesis for AHR, although when increased in mass it may contribute to AHR. The inability of a deep breath to reverse or prevent bronchial narrowing in asthma may reflect an intrinsic difference in the mechanisms that lead to softening of contracted ASM when subjected to stretch. Cytokines such as interleukin-13 and tumor necrosis factor-α promote a more contractile ASM phenotype. The composition and increased stiffness of the matrix in which ASM is embedded promotes a more proliferative and pro-inflammatory ASM phenotype, but the expected dedifferentiation and loss of contractility have not been shown. Airway epithelium may drive ASM proliferation and/or molecular remodeling in ways that may lead to AHR. In conclusion, AHR is likely multifactorial in origin, reflecting the plasticity of ASM properties in the inflammatory environment of the asthmatic airway.
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Hamann, Kimm J., Joaquim E. Vieira, Andrew J. Halayko, Delbert Dorscheid, Steven R. White, Sean M. Forsythe, Blanca Camoretti-Mercado, Klaus F. Rabe, and Julian Solway. "Fas cross-linking induces apoptosis in human airway smooth muscle cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 278, no. 3 (March 1, 2000): L618—L624. http://dx.doi.org/10.1152/ajplung.2000.278.3.l618.
Full textAbstract:
Hypertrophy and hyperplasia lead to excess accumulation of smooth muscle in the airways of human asthmatic subjects. However, little is known about mechanisms that might counterbalance these processes, thereby limiting the quantity of smooth muscle in airways. Ligation of Fas on the surface of vascular smooth muscle cells and nonmuscle airway cells can lead to apoptotic cell death. We therefore tested the hypotheses that 1) human airway smooth muscle (HASM) expresses Fas, 2) Fas cross-linking induces apoptosis in these cells, and 3) tumor necrosis factor (TNF)-α potentiates Fas-mediated airway myocyte killing. Immunohistochemistry using CH-11 anti-Fas monoclonal IgM antibody revealed Fas expression in normal human bronchial smooth muscle in vivo. Flow cytometry using DX2 anti-Fas monoclonal IgG antibody revealed that passage 4 cultured HASM cells express surface Fas. Surface Fas decreased partially during prolonged serum deprivation of cultured HASM cells and was upregulated by TNF-α stimulation. Fas cross-linking with CH-11 antibody induced apoptosis in cultured HASM cells, and this effect was reduced by long-term serum deprivation and synergistically potentiated by concomitant TNF-α exposure. TNF-α did not induce substantial apoptosis in the absence of Fas cross-linking. These data represent the first demonstration that Fas is expressed on HASM and suggest a mechanism by which Fas-mediated apoptosis could act to oppose excess smooth muscle accumulation during airway remodeling in asthma.
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Kc, Prabha, Catherine A. Mayer, and Musa A. Haxhiu. "Chemical profile of vagal preganglionic motor cells innervating the airways in ferrets: the absence of noncholinergic neurons." Journal of Applied Physiology 97, no. 4 (October 2004): 1508–17. http://dx.doi.org/10.1152/japplphysiol.00282.2004.
Full textAbstract:
In ferrets, we investigated the presence of choline acetyltransferase (ChAT), vasoactive intestinal peptide (VIP), and markers for nitric oxide synthase (NOS) in preganglionic parasympathetic neurons innervating extrathoracic trachea and intrapulmonary airways. Cholera toxin β-subunit, a retrograde axonal transganglionic tracer, was used to identify airway-related vagal preganglionic neurons. Double-labeling immunohistochemistry and confocal microscopy were employed to characterize the chemical nature of identified airway-related vagal preganglionic neurons at a single cell level. Physiological experiments were performed to determine whether activation of the VIP and ChAT coexpressing vagal preganglionic neurons plays a role in relaxation of precontracted airway smooth muscle tone after muscarinic receptor blockade. The results showed that 1) all identified vagal preganglionic neurons innervating extrathoracic and intrapulmonary airways are acetylcholine-producing cells, 2) cholinergic neurons innervating the airways coexpress ChAT and VIP but do not contain NOS, and 3) chemical stimulation of the rostral nucleus ambiguus had no significant effect on precontracted airway smooth muscle tone after muscarinic receptor blockade. These studies indicate that vagal preganglionic neurons are cholinergic in nature and coexpress VIP but do not contain NOS; their stimulation increases cholinergic outflow, without activation of inhibitory nonadrenergic, noncholinergic ganglionic neurons, stimulation of which induces airway smooth muscle relaxation. Furthermore, these studies do not support the possibility of direct inhibitory innervation of airway smooth muscle by vagal preganglionic fibers that contain VIP.
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Kong, S. K., A. J. Halayko, and N. L. Stephens. "Increased myosin phosphorylation in sensitized canine tracheal smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 259, no. 2 (August 1, 1990): L53—L56. http://dx.doi.org/10.1152/ajplung.1990.259.2.l53.
Full textAbstract:
We have reported that the maximal velocity of shortening and myofibrillar adenosine triphosphatase (ATPase) activity of antigen-sensitized airway smooth muscle are higher than that of nonsensitized airway smooth muscle (Kong, S. K., R. P. C. Shiu, and N. L. Stephens. J. Appl. Physiol. 60: 92–94, 1986). To extend these studies, we attempted to determine whether the increased myofibrillar ATPase activity from sensitized airway smooth muscle was associated with either a change in distribution of two myosin heavy chain isozymes or an increase in myosin light chain phosphorylation. Myosin heavy chain isozymes from both control and sensitized airway smooth muscle were separated by 4% sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Gels were analyzed by densitometry, which indicated that isozyme band pattern of sensitized airway smooth muscle was not different from that of the control. The maximal levels of phosphorylated myosin light chain from whole cell homogenates of sensitized and control tracheal smooth muscles were 0.65 +/- 0.029 (n = 6) and 0.40 +/- 0.025 mol Pi/mol light chain (n = 6), respectively. The degree of phosphorylation of myosin light chain of sensitized airway smooth muscle was significantly higher than that of the control (P less than 0.05). This study also indicated that increased myofibrillar ATPase activity in sensitized tracheal smooth muscle was correlated with phosphorylation of myosin light chain.
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Pratusevich, V. R., C. Y. Seow, and L. E. Ford. "Plasticity in canine airway smooth muscle." Journal of General Physiology 105, no. 1 (January 1, 1995): 73–94. http://dx.doi.org/10.1085/jgp.105.1.73.
Full textAbstract:
The large volume changes of some hollow viscera require a greater length range for the smooth muscle of their walls than can be accommodated by a fixed array of sliding filaments. A possible explanation is that smooth muscles adapt to length changes by forming variable numbers of contractile units in series. To test for such plasticity we examined the muscle length dependence of shortening velocity and compliance, both of which will vary directly with the number of thick filaments in series. Dog tracheal smooth muscle was studied because its cells are arrayed in long, straight, parallel bundles that span the length of the preparation. In experiments where muscle length was changed, both compliance and velocity showed a strong dependence on muscle length, varying by 1.7-fold and 2.2-fold, respectively, over a threefold range of length. The variation in isometric force was substantially less, ranging from a 1.2- to 1.3-fold in two series of experiments where length was varied by twofold to an insignificant 4% variation in a third series where a threefold length range was studied. Tetanic force was below its steady level after both stretches and releases, and increased to a steady level with 5-6 tetani at 5 min intervals. These results suggest strongly that the number of contractile units in series varies directly with the adapted muscle length. Temporary force depression after a length change would occur if the change transiently moved the filaments from their optimum overlap. The relative length independence of the adapted force is explained by the reforming of the filament lattice to produce optimum force development, with commensurate changes of velocity and compliance.
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Halayko, A. J., H. Salari, X. MA, and N. L. Stephens. "Markers of airway smooth muscle cell phenotype." American Journal of Physiology-Lung Cellular and Molecular Physiology 270, no. 6 (June 1, 1996): L1040—L1051. http://dx.doi.org/10.1152/ajplung.1996.270.6.l1040.
Full textAbstract:
Airway smooth muscle plays a principal role in the pathogenesis of asthma. Primary cultures are being used to investigate airway myocyte proliferation and cellular pathways regulating contraction. Airway smooth muscle cells (SMC) modulate from a contractile to a noncontractile phenotype in culture, but no systematic study of the concomitant changes in expression of cytocontractile and cytoskeletal proteins has been reported. We measured temporal changes in protein marker expression of canine tracheal SMC in primary culture, using specific antibodies and cDNA probes. Immunoblot analysis revealed that when cells became proliferative after 5 days of culture, the content of smooth muscle myosin heavy chain (sm-MHC), calponin, sm-alpha-actin, and desmin diminished by > 75%; myosin light chain kinase, h-caldesmon, and beta-tropomyosin had also decreased significantly (P < 0.05). Northern blots revealed that mRNA levels for sm-MHC and sm-alpha-actin were also significantly reduced in proliferative SMC. Conversely, immunoblotting demonstrated the content of non-muscle myosin heavy chain, l-caldesmon, vimentin, alpha/beta-protein kinase C (PKC), and CD44 homing cellular adhesion molecule (HCAM) increased one- to sixfold as cells became proliferative. The content of sm-MHC and sm-alpha-actin protein increased after confluence, suggesting that cultured airway SMC are capable of phenotypic plasticity. Marker protein contents were also compared, by immunoblot assay, between SMC dissociated from trachealis or pulmonary arterial media. Cytocontractile protein content was higher in the trachea, which shortens faster than the pulmonary artery. The identification of these markers provides tools for assessing the phenotype of airway SMC in culture and the airways of asthmatic patients.
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Szarek, J. L., H. L. Ramsay, A. Andringa, and M. L. Miller. "Time course of airway hyperresponsiveness and remodeling induced by hyperoxia in rats." American Journal of Physiology-Lung Cellular and Molecular Physiology 269, no. 2 (August 1, 1995): L227—L233. http://dx.doi.org/10.1152/ajplung.1995.269.2.l227.
Full textAbstract:
The purpose of this study was to answer two questions concerning hyperoxia-induced airway hyperresponsiveness: 1) What is the time course of the development of airway hyperresponsiveness? 2) What is the relationship between the increase in responsiveness and smooth muscle area? Segments of intrapulmonary bronchi were isolated from male Sprague-Dawley rats that had been exposed to 80-85% O2 for a period of 1, 3, 5, or 7 days and from aged-matched control animals that breathed room air. Hyperoxia increased the sensitivity (log concentration or frequency that elicited a half-maximal response) and reactivity (maximum tension developed) of the airways to electrical field stimulation (EFS) after 3, 5, and 7 days; sensitivity to acetylcholine was not affected, but reactivity was increased after 7 days. Hyperoxia increased smooth muscle area beginning 5 days after commencing the exposure. After normalizing tension responses to smooth muscle area, reactivity of the airways to the stimuli was not different between the two groups, but sensitivity to EFS was still increased. The increase in reactivity observed after 5 and 7 days of exposure can be explained by an increase in smooth muscle area that occurred at these time points. The fact that the sensitivity of the airways to EFS remained increased after normalization, together with the fact that the increase in airway responsiveness after 3 days of exposure occurred at a time when smooth muscle area was not different from control, suggests that mechanisms other than increased smooth muscle area contribute to the development of hyperoxia-induced airway hyperresponsiveness.
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Emala, C. W., A. Aryana, M. A. Levine, R. P. Yasuda, S. A. Satkus, B. B. Wolfe, and C. A. Hirshman. "Basenji-greyhound dog: increased m2 muscarinic receptor expression in trachealis muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 268, no. 6 (June 1, 1995): L935—L940. http://dx.doi.org/10.1152/ajplung.1995.268.6.l935.
Full textAbstract:
Airway smooth muscle from asthmatic humans and from the Basenji-greyhound dog (BG) dog is hyporesponsive to beta-adrenergic agonist stimulation. Because adenylyl cyclase is under dual regulation in airway smooth muscle, we compared muscarinic receptor-coupled inhibition of adenylyl cyclase in airway smooth muscle from BG and mongrel dogs. Inhibition of forskolin-stimulated adenylyl cyclase activity by the muscarinic M2 agonist oxotremorine was greater in airway smooth muscle membranes from BG compared with mongrel controls. Quantitative immunoprecipitation studies showed increased numbers of m2 but not m3 muscarinic receptors in the BG airway smooth muscle. The enhanced ability of muscarinic agonists to inhibit adenylyl cyclase in BG airway smooth muscle may be due to the greater numbers of muscarinic m2 receptors, which may account in part for impaired airway smooth muscle relaxation in the BG model of airway hyperresponsiveness.
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Hasaneen, Nadia A., Stanley Zucker, Richard Z. Lin, Gayle G. Vaday, Reynold A. Panettieri, and Hussein D. Foda. "Angiogenesis is induced by airway smooth muscle strain." American Journal of Physiology-Lung Cellular and Molecular Physiology 293, no. 4 (October 2007): L1059—L1068. http://dx.doi.org/10.1152/ajplung.00480.2006.
Full textAbstract:
Angiogenesis is an important feature of airway remodeling in both chronic asthma and chronic obstructive pulmonary disease (COPD). Airways in those conditions are exposed to excessive mechanical strain during periods of acute exacerbations. We recently reported that mechanical strain of human airway smooth muscle (HASM) led to an increase in their proliferation and migration. Sustained growth in airway smooth muscle in vivo requires an increase in the nutritional supply to these muscles, hence angiogenesis. In this study, we examined the hypothesis that cyclic mechanical strain of HASM produces factors promoting angiogenic events in the surrounding vascular endothelial cells. Our results show: 1) a significant increase in human lung microvascular endothelial cell (HMVEC-L) proliferation, migration, and tube formation following incubation in conditioned media (CM) from HASM cells exposed to mechanical strain; 2) mechanical strain of HASM cells induced VEGF expression and release; 3) VEGF neutralizing antibodies inhibited the proliferation, migration, and tube formations of HMVEC-L induced by the strained airway smooth muscle CM; 4) mechanical strain of HASM induced a significant increase in hypoxia-inducible factor-1α (HIF-1α) mRNA and protein, a transcription factor required for VEGF gene transcription; and 5) mechanical strain of HASM induced HIF-1α/VEGF through dual phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and ERK pathways. In conclusion, exposing HASM cells to mechanical strain induces signal transduction pathway through PI3K/Akt/mTOR and ERK pathways that lead to an increase in HIF-1α, a transcription factor required for VEGF expression. VEGF release by mechanical strain of HASM may contribute to the angiogenesis seen with repeated exacerbation of asthma and COPD.
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Shioya, T., N. M. Munoz, and A. R. Leff. "Effect of resting smooth muscle length on contractile response in resistance airways." Journal of Applied Physiology 62, no. 2 (February 1, 1987): 711–17. http://dx.doi.org/10.1152/jappl.1987.62.2.711.
Full textAbstract:
We studied the effect of resting smooth muscle length on the contractile response of the major resistance airways (generations 0–5) in 18 mongrel dogs in vivo using tantalum bronchography. Dose-response curves to 10(-10) to 10(-7) mol/kg methacholine (MCh) were generated [at functional residual capacity (FRC)] by repeated intravenous bolus administration using tantalum bronchography after each dose. Airway constriction varied substantially with dose-equivalent stimulation and varied sequentially from trachea (8.8 +/- 2.2% change in airway diam) to fifth-generation bronchus (49.8 +/- 3.0%; P less than 0.001). Length-tension curves were generated for each airway to determine the airway diameter (i.e., resting in situ smooth muscle length) at which maximal constriction was elicited using bolus intravenous injection of 10(-8) mol/kg MCh. A Frank-Starling relationship was obtained for each airway; the transpulmonary pressure at which maximal constriction was elicited increased progressively from 2.50 +/- 1.12 cmH2O for trachea (approximately FRC) to 18.3 +/- 1.05 cmH2O for fifth-generation airways (approximately 50% TLC) (P less than 0.001). A similar relationship was obtained when change in airway diameter was plotted as a function of airway radius. We demonstrate substantial heterogeneity in the lung volumes at which maximal constriction is elicited and in distribution of parasympathomimetic constriction within the first few generations of resistance bronchi. Our data also suggest that lung hyperinflation may lead to augmented airway contractile responses by shifting resting smooth muscle length toward optimum resting smooth muscle length.
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Gallos, George, Peter Yim, Sucie Chang, Yi Zhang, Dingbang Xu, James M. Cook, William T. Gerthoffer, and Charles W. Emala. "Targeting the restricted α-subunit repertoire of airway smooth muscle GABAA receptors augments airway smooth muscle relaxation." American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no. 2 (January 15, 2012): L248—L256. http://dx.doi.org/10.1152/ajplung.00131.2011.
Full textAbstract:
The prevalence of asthma has taken on pandemic proportions. Since this disease predisposes patients to severe acute airway constriction, novel mechanisms capable of promoting airway smooth muscle relaxation would be clinically valuable. We have recently demonstrated that activation of endogenous airway smooth muscle GABAA receptors potentiates β-adrenoceptor-mediated relaxation, and molecular analysis of airway smooth muscle reveals that the α-subunit component of these GABAA receptors is limited to the α4- and α5-subunits. We questioned whether ligands with selective affinity for these GABAA receptors could promote relaxation of airway smooth muscle. RT-PCR analysis of GABAA receptor subunits was performed on RNA isolated by laser capture microdissection from human and guinea pig airway smooth muscle. Membrane potential and chloride-mediated current were measured in response to GABAA subunit-selective agonists in cultured human airway smooth muscle cells. Functional relaxation of precontracted guinea pig tracheal rings was assessed in the absence and presence of the α4-subunit-selective GABAA receptor agonists: gaboxadol, taurine, and a novel 8-methoxy imidazobenzodiazepine (CM-D-45). Only messenger RNA encoding the α4- and α5-GABAA receptor subunits was identified in RNA isolated by laser capture dissection from guinea pig and human airway smooth muscle tissues. Activation of airway smooth muscle GABAA receptors with agonists selective for these subunits resulted in appropriate membrane potential changes and chloride currents and promoted relaxation of airway smooth muscle. In conclusion, selective subunit targeting of endogenous airway smooth muscle-specific GABAA receptors may represent a novel therapeutic option for patients in severe bronchospasm.
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Brown, R. H., and W. Mitzner. "Effect of lung inflation and airway muscle tone on airway diameter in vivo." Journal of Applied Physiology 80, no. 5 (May 1, 1996): 1581–88. http://dx.doi.org/10.1152/jappl.1996.80.5.1581.
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How normal airway dimensions change with lung volume is of great importance in determining flow limitation during the normal forced vital capacity maneuver as well as in the manifestation of obstructive lung disease. The literature presents a confusing picture, with some results suggesting that airway diameter increases linearly with the cube root of lung volume and others showing a highly nonlinear relation. The effect of smooth muscle contraction on lung-airway interdependence is even less well understood. Recent morphological work explicitly assumes that airway basement membrane is nondistensible, although the lung volume at which this maximal airway size is reached is unknown. With smooth muscle contraction, folding of the epithelium and basement membrane accounts for the changes in luminal area. In this study, we measured the effect of lung inflation on relaxed and contracted airway areas by using high-resolution computed tomography at different transpulmonary pressures, each held for 2 min. We found that fully relaxed airways are quite distensible up to a pressure of 5-7 cmH2O (P < 0.001), where they reach a maximal size with no further distension up to an airway pressure of 30 cmH2O (P = 0.49). Thus relaxed airways clearly do not expand isotropically with the lung. With smooth muscle tone, the airways in different animals responded differently to lung inflation, with some animals showing minimal airway dilation up to an airway pressure of 20 cmH2O and others showing airways that were more easily dilated with lung expansion. However, maximal diameter of these moderately constricted airways was not usually achieved even up to an airway pressure of 30 cmH2O. Thus a transient deep inspiration in vivo would be expected to have only a small effect on contracted airways.
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Oliver, Brian G., and Judith L. Black. "Airway Smooth Muscle and Asthma." Allergology International 55, no. 3 (2006): 215–23. http://dx.doi.org/10.2332/allergolint.55.215.
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Hershenson, Marc B., Melanie Brown, Blanca Camoretti-Mercado, and Julian Solway. "Airway Smooth Muscle in Asthma." Annual Review of Pathology: Mechanisms of Disease 3, no. 1 (February 2008): 523–55. http://dx.doi.org/10.1146/annurev.pathmechdis.1.110304.100213.
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FREDBERG, JEFFREY J. "Airway Smooth Muscle in Asthma." American Journal of Respiratory and Critical Care Medicine 161, supplement_2 (March 2000): S158—S160. http://dx.doi.org/10.1164/ajrccm.161.supplement_2.a1q4-1.
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Laitinen, Lauri A., and Annika Laitinen. "Innervation of Airway Smooth Muscle." American Review of Respiratory Disease 136, no. 4_pt_2 (October 1987): S38—S42. http://dx.doi.org/10.1164/ajrccm/136.4_pt_2.s38.
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