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Regulation of Airway Smooth Muscle Contraction in Health and Disease

  • Maggie Lam
  • Emma Lamanna
  • Jane E. BourkeEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1124)

Abstract

Airway smooth muscle (ASM) extends from the trachea throughout the bronchial tree to the terminal bronchioles. In utero, spontaneous phasic contraction of fetal ASM is critical for normal lung development by regulating intraluminal fluid movement, ASM differentiation, and release of key growth factors. In contrast, phasic contraction appears to be absent in the adult lung, and regulation of tonic contraction and airflow is under neuronal and humoral control. Accumulating evidence suggests that changes in ASM responsiveness contribute to the pathophysiology of lung diseases with lifelong health impacts.

Functional assessments of fetal and adult ASM and airways have defined pharmacological responses and signaling pathways that drive airway contraction and relaxation. Studies using precision-cut lung slices, in which contraction of intrapulmonary airways and ASM calcium signaling can be assessed simultaneously in situ, have been particularly informative. These combined approaches have defined the relative importance of calcium entry into ASM and calcium release from intracellular stores as drivers of spontaneous phasic contraction in utero and excitation-contraction coupling.

Increased contractility of ASM in asthma contributes to airway hyperresponsiveness. Studies using animal models and human ASM and airways have characterized inflammatory and other mechanisms underlying increased reactivity to contractile agonists and reduced bronchodilator efficacy of β2-adrenoceptor agonists in severe diseases. Novel bronchodilators and the application of bronchial thermoplasty to ablate increased ASM within asthmatic airways have the potential to overcome limitations of current therapies. These approaches may directly limit excessive airway contraction to improve outcomes for difficult-to-control asthma and other chronic lung diseases.

Keywords

Airway smooth muscle Phasic Tonic Contraction Calcium Bronchodilator Asthma 

References

  1. 1.
    Hislop AA. Airway and blood vessel interaction during lung development. J Anat. 2002;201(4):325–34.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Zoetis T, Hurtt ME. Species comparison of lung development. Birth Defects Res B Dev Reprod Toxicol. 2003;68(2):121–4.PubMedCrossRefGoogle Scholar
  3. 3.
    Leslie KO, Mitchell JJ, Woodcock-Mitchell JL, Low RB. Alpha smooth muscle actin expression in developing and adult human lung. Differentiation. 1990;44(2):143–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Ochs M, Nyengaard JR, Jung A, Knudsen L, Voigt M, Wahlers T, et al. The number of alveoli in the human lung. Am J Respir Crit Care Med. 2004;169(1):120–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Macklem PT, Mead J. Resistance of central and peripheral airways measured by a retrograde catheter. J Appl Physiol. 1967;22(3):395–401.PubMedCrossRefGoogle Scholar
  6. 6.
    Braido F, Scichilone N, Lavorini F, Usmani OS, Dubuske L, Boulet LP, et al. Manifesto on small airway involvement and management in asthma and chronic obstructive pulmonary disease: an Interasma (Global Asthma Association—GAA) and World Allergy Organization (WAO) document endorsed by Allergic Rhinitis and its Impact on Asthma (ARIA) and Global Allergy and Asthma European Network (GA(2)LEN). World Allergy Organ J. 2016;9(1):37.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Mailleux AA, Kelly R, Veltmaat JM, De Langhe SP, Zaffran S, Thiery JP, et al. Fgf10 expression identifies parabronchial smooth muscle cell progenitors and is required for their entry into the smooth muscle cell lineage. Development. 2005;132(9):2157–66.PubMedCrossRefGoogle Scholar
  8. 8.
    Shan L, Subramaniam M, Emanuel R, Degan S, Johnston P, Tefft D, et al. Centrifugal migration of mesenchymal cells in embryonic lung. Dev Dyn. 2008;237(3):750–7.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Pandya HC, Innes J, Hodge R, Bustani P, Silverman M, Kotecha S. Spontaneous contraction of pseudoglandular-stage human airspaces is associated with the presence of smooth muscle-alpha-actin and smooth muscle-specific myosin heavy chain in recently differentiated fetal human airway smooth muscle. Biol Neonate. 2006;89(4):211–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Yang Y, Beqaj S, Kemp P, Ariel I, Schuger L. Stretch-induced alternative splicing of serum response factor promotes bronchial myogenesis and is defective in lung hypoplasia. J Clin Invest. 2000;106(11):1321–30.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Schittny JC, Miserocchi G, Sparrow MP. Spontaneous peristaltic airway contractions propel lung liquid through the bronchial tree of intact and fetal lung explants. Am J Respir Cell Mol Biol. 2000;23(1):11–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Sparrow MP, Lamb JP. Ontogeny of airway smooth muscle: structure, innervation, myogenesis and function in the fetal lung. Respir Physiol Neurobiol. 2003;137(2–3):361–72.PubMedCrossRefGoogle Scholar
  13. 13.
    van der Velden VH, Hulsmann AR. Autonomic innervation of human airways: structure, function, and pathophysiology in asthma. Neuroimmunomodulation. 1999;6(3):145–59.PubMedCrossRefGoogle Scholar
  14. 14.
    Lewis M. Spontaneous rhythmical contractions of the muscle of the bronchial tubes and air sacs of the chick embryo. Am J Physiol. 1924;68:385–8.CrossRefGoogle Scholar
  15. 15.
    Richards IS, Kulkarni A, Brooks SM. Human fetal tracheal smooth muscle produces spontaneous electromechanical oscillations that are Ca2+ dependent and cholinergically potentiated. Dev Pharmacol Ther. 1991;16(1):22–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Roman J. Effects of calcium channel blockade on mammalian lung branching morphogenesis. Exp Lung Res. 1995;21(4):489–502.PubMedCrossRefGoogle Scholar
  17. 17.
    Yang Y, Palmer KC, Relan N, Diglio C, Schuger L. Role of laminin polymerization at the epithelial mesenchymal interface in bronchial myogenesis. Development. 1998;125(14):2621–9.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Jesudason EC. Airway smooth muscle: an architect of the lung? Thorax. 2009;64(6):541–5.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Hooper SB, Harding R. Fetal lung liquid: a major determinant of the growth and functional development of the fetal lung. Clin Exp Pharmacol Physiol. 1995;22(4):235–47.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Nardo L, Hooper SB, Harding R. Stimulation of lung growth by tracheal obstruction in fetal sheep: relation to luminal pressure and lung liquid volume. Pediatr Res. 1998;43(2):184–90.PubMedCrossRefGoogle Scholar
  21. 21.
    Badri KR, Zhou Y, Schuger L. Embryological origin of airway smooth muscle. Proc Am Thorac Soc. 2008;5(1):4–10.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Jesudason EC, Smith NP, Connell MG, Spiller DG, White MR, Fernig DG, et al. Developing rat lung has a sided pacemaker region for morphogenesis-related airway peristalsis. Am J Respir Cell Mol Biol. 2005;32(2):118–27.PubMedCrossRefGoogle Scholar
  23. 23.
    Snetkov VA, Pandya H, Hirst SJ, Ward JP. Potassium channels in human fetal airway smooth muscle cells. Pediatr Res. 1998;43(4 Pt 1):548–54.PubMedCrossRefGoogle Scholar
  24. 24.
    Janssen LJ. Ionic mechanisms and Ca2+ regulation in airway smooth muscle contraction: do the data contradict dogma? Am J Physiol. 2002;282:L1161–78.CrossRefGoogle Scholar
  25. 25.
    Ito Y, Suzuki H, Aizawa H, Hakoda H, Hirose T. The spontaneous electrical and mechanical activity of human bronchial smooth muscle: its modulation by drugs. Br J Pharmacol. 1989;98(4):1249–60.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    McCray PB. Spontaneous Contractility of Human Fetal Airway Smooth Muscle. Am J Respir Cell Mol Biol. 1993;8(5):573–80.PubMedCrossRefGoogle Scholar
  27. 27.
    Featherstone NC, Jesudason EC, Connell MG, Fernig DG, Wray S, Losty PD, et al. Spontaneous propagating calcium waves underpin airway peristalsis in embryonic rat lung. Am J Respir Cell Mol Biol. 2005;33(2):153–60.PubMedCrossRefGoogle Scholar
  28. 28.
    Matsumoto H, Hirata Y, Otsuka K, Iwata T, Inazumi A, Niimi A, et al. Interleukin-13 enhanced Ca2+ oscillations in airway smooth muscle cells. Cytokine. 2012;57(1):19–24.PubMedCrossRefGoogle Scholar
  29. 29.
    Sweeney D, Hollins F, Gomez E, Saunders R, Challiss RA, Brightling CE. [Ca2+]i oscillations in ASM: relationship with persistent airflow obstruction in asthma. Respirology. 2014;19(5):763–6.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Linden A, Lofdahl CG, Ullman A, Skoogh BE. In vitro characteristics of spontaneous airway tone in the guinea-pig. Acta Physiol Scand. 1991;142(3):351–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Hartman WR, Smelter DF, Sathish V, Karass M, Kim S, Aravamudan B, et al. Oxygen dose responsiveness of human fetal airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2012;303(8):L711–9.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Mitzner W. Airway smooth muscle: the appendix of the lung. Am J Respir Crit Care Med. 2004;169(7):787–90.PubMedCrossRefGoogle Scholar
  33. 33.
    Seow CY, Fredberg JJ. Historical perspective on airway smooth muscle: the saga of a frustrated cell. J Appl Physiol (1985). 2001;91(2):938–52.CrossRefGoogle Scholar
  34. 34.
    James AL, Hogg JC, Dunn LA, Pare PD. The use of the internal perimeter to compare airway size and to calculate smooth muscle shortening. Am Rev Respir Dis. 1988;138(1):136–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Widdicombe JG. Regulation of tracheobronchial smooth muscle. Physiol Rev. 1963;43:1–37.PubMedCrossRefGoogle Scholar
  36. 36.
    Nadel JA, Widdicombe JG. Reflex control of airway size. Ann N Y Acad Sci. 1963;109:712–23.PubMedCrossRefGoogle Scholar
  37. 37.
    Woolcock AJ, Salome CM, Yan K. The shape of the dose-response curve to histamine in asthmatic and normal subjects. Am Rev Respir Dis. 1984;130(1):71–5.PubMedGoogle Scholar
  38. 38.
    Wright D, Sharma P, Ryu MH, Risse PA, Ngo M, Maarsingh H, et al. Models to study airway smooth muscle contraction in vivo, ex vivo and in vitro: implications in understanding asthma. Pulm Pharmacol Ther. 2013;26(1):24–36.CrossRefGoogle Scholar
  39. 39.
    Sanderson MJ. Exploring lung physiology in health and disease with lung slices. Pulm Pharmacol Ther. 2011;24(5):452–65.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Schlepütz M, Rieg AD, Seehase S, Spillner J, Perez-Bouza A, Braunschweig T, et al. Neurally mediated airway constriction in human and other species: a comparative study using precision-cut lung slices (PCLS). PLoS One. 2012;7(10):e47344.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    An SS, Mitzner W, Tang WY, Ahn K, Yoon AR, Huang J, et al. An inflammation-independent contraction mechanophenotype of airway smooth muscle in asthma. J Allergy Clin Immunol. 2016;138(1):294–7.e4.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Hirst SJ, Martin JG, Bonacci JV, Chan V, Fixman ED, Hamid QA, et al. Proliferative aspects of airway smooth muscle. J Allergy Clin Immunol. 2004;114(2 Suppl):S2–17.PubMedCrossRefGoogle Scholar
  43. 43.
    Howarth PH, Knox AJ, Amrani Y, Tliba O, Panettieri RA Jr, Johnson M. Synthetic responses in airway smooth muscle. J Allergy Clin Immunol. 2004;114(2 Suppl):S32–50.PubMedCrossRefGoogle Scholar
  44. 44.
    Spicuzza L, Giembycz MA, Barnes PJ, Belvisi MG. Prostaglandin E2 suppression of acetylcholine release from parasympathetic nerves innervating guinea-pig trachea by interacting with prostanoid receptors of the EP3-subtype. Br J Pharmacol. 1998;123(6):1246–52.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Clarke DL, Dakshinamurti S, Larsson AK, Ward JE, Yamasaki A. Lipid metabolites as regulators of airway smooth muscle function. Pulm Pharmacol Ther. 2009;22(5):426–35.PubMedCrossRefGoogle Scholar
  46. 46.
    Johnson PR. Role of human airway smooth muscle in altered extracellular matrix production in asthma. Clin Exp Pharmacol Physiol. 2001;28(3):233–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Ward JE, Hirst SJ. Airway smooth muscle bidirectional interactions with extracellular matrix. In: Chung KF, editor. Airway smooth muscle biology and pharmacology in airways disease. Chichester: Wiley; 2007. p. 105–26.Google Scholar
  48. 48.
    Canning BJ. Reflex regulation of airway smooth muscle tone. J Appl Physiol (1985). 2006;101(3):971–85.CrossRefGoogle Scholar
  49. 49.
    Barnes PJ, Basbaum CB, Nadel JA. Autoradiographic localization of autonomic receptors in airway smooth muscle. Marked differences between large and small airways. Am Rev Respir Dis. 1983;127(6):758–62.PubMedGoogle Scholar
  50. 50.
    Zaagsma J, Roffel AF, Meurs H. Muscarinic control of airway function. Life Sci. 1997;60(13–14):1061–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Taylor SM, Pare PD, Schellenberg RR. Cholinergic and nonadrenergic mechanisms in human and guinea pig airways. J Appl Physiol Respir Environ Exerc Physiol. 1984;56(4):958–65.PubMedGoogle Scholar
  52. 52.
    Mitchell RA, Herbert DA, Baker DG, Basbaum CB. In vivo activity of tracheal parasympathetic ganglion cells innervating tracheal smooth muscle. Brain Res. 1987;437(1):157–60.PubMedCrossRefGoogle Scholar
  53. 53.
    Seehase S, Schleputz M, Switalla S, Matz-Rensing K, Kaup FJ, Zoller M, et al. Bronchoconstriction in nonhuman primates: a species comparison. J Appl Physiol (1985). 2011;111(3):791–8.CrossRefGoogle Scholar
  54. 54.
    Lambermont VA, Schleputz M, Dassow C, Konig P, Zimmermann LJ, Uhlig S, et al. Comparison of airway responses in sheep of different age in precision-cut lung slices (PCLS). PLoS One. 2014;9(9):e97610.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Chitano P, Murphy TM. Maturational changes in airway smooth muscle shortening and relaxation. Implications for asthma. Respir Physiol Neurobiol. 2003;137(2–3):347–59.PubMedCrossRefGoogle Scholar
  56. 56.
    Finney MJ, Karlsson JA, Persson CG. Effects of bronchoconstrictors and bronchodilators on a novel human small airway preparation. Br J Pharmacol. 1985;85(1):29–36.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Martin C, Uhlig S, Ullrich V. Videomicroscopy of methacholine-induced contraction of individual airways in precision-cut lung slices. Eur Respir J. 1996;9(12):2479–87.PubMedCrossRefGoogle Scholar
  58. 58.
    Noble PB, McLaughlin RA, West AR, Becker S, Armstrong JJ, McFawn PK, et al. Distribution of airway narrowing responses across generations and at branching points, assessed in vitro by anatomical optical coherence tomography. Respir Res. 2010;11:9.Google Scholar
  59. 59.
    Bai Y, Zhang M, Sanderson MJ. Contractility and Ca2+ signaling of smooth muscle cells in different generations of mouse airways. Am J Respir Cell Mol Biol. 2007;36(1):122–30.PubMedCrossRefGoogle Scholar
  60. 60.
    Sparrow MP, Weichselbaum M. Structure and function of the adventitial and mucosal nerve plexuses of the bronchial tree in the developing lung. Clin Exp Pharmacol Physiol. 1997;24(3–4):261–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Sheldrick RL, Ball DI, Coleman RA. Characterisation of the neurokinin receptors mediating contraction of isolated tracheal preparations from a variety of species. Agents Actions Suppl. 1990;31:205–9.PubMedGoogle Scholar
  62. 62.
    Advenier C, Naline E, Toty L, Bakdach H, Emonds-Alt X, Vilain P, et al. Effects on the isolated human bronchus of SR 48968, a potent and selective nonpeptide antagonist of the neurokinin A (NK2) receptors. Am Rev Respir Dis. 1992;146(5 Pt 1):1177–81.PubMedCrossRefGoogle Scholar
  63. 63.
    Amadesi S, Moreau J, Tognetto M, Springer J, Trevisani M, Naline E, et al. NK1 receptor stimulation causes contraction and inositol phosphate increase in medium-size human isolated bronchi. Am J Respir Crit Care Med. 2001;163(5):1206–11.PubMedCrossRefGoogle Scholar
  64. 64.
    Palmer JB, Cuss FM, Mulderry PK, Ghatei MA, Springall DR, Cadieux A, et al. Calcitonin gene-related peptide is localised to human airway nerves and potently constricts human airway smooth muscle. Br J Pharmacol. 1987;91(1):95–101.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Springer J, Amadesi S, Trevisani M, Harrison S, Dinh QT, McGregor GP, et al. Effects of alpha calcitonin gene-related peptide in human bronchial smooth muscle and pulmonary artery. Regul Pept. 2004;118(3):127–34.PubMedCrossRefGoogle Scholar
  66. 66.
    Sheppard MN, Marangos PJ, Bloom SR, Polak JM. Neuron specific enolase: a marker for the early development of nerves and endocrine cells in the human lung. Life Sci. 1984;34(3):265–71.PubMedCrossRefGoogle Scholar
  67. 67.
    O’Donnell SR, Saar N. Histochemical localization of adrenergic nerves in the guinea-pig trachea. Br J Pharmacol. 1973;47(4):707–10.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Mitchell HW, Sparrow MP, Tagliaferri RP. Inhibitory and excitatory responses to field stimulation in fetal and adult pig airway. Pediatr Res. 1990;28(1):69–74.PubMedCrossRefGoogle Scholar
  69. 69.
    Doidge JM, Satchell DG. Adrenergic and non-adrenergic inhibitory nerves in mammalian airways. J Auton Nerv Syst. 1982;5(2):83–99.PubMedCrossRefGoogle Scholar
  70. 70.
    Cadieux A, Benchekroun MT, St-Pierre S, Fournier A. Bronchoconstrictor action of neuropeptide Y (NPY) in isolated guinea pig airways. Neuropeptides. 1989;13(4):215–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Li S, Koziol-White C, Jude J, Jiang M, Zhao H, Cao G, et al. Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness. J Clin Invest. 2016;126(5):1978–82.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Henry PJ, Goldie RG. Beta 1-adrenoceptors mediate smooth muscle relaxation in mouse isolated trachea. Br J Pharmacol. 1990;99(1):131–5.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Carstairs JR, Nimmo AJ, Barnes PJ. Autoradiographic visualization of beta-adrenoceptor subtypes in human lung. Am Rev Respir Dis. 1985;132(3):541–7.PubMedGoogle Scholar
  74. 74.
    Carswell H, Nahorski SR. Beta-adrenoceptor heterogeneity in guinea-pig airways: comparison of functional and receptor labelling studies. Br J Pharmacol. 1983;79(4):965–71.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Palmer JB, Cuss FM, Barnes PJ. VIP and PHM and their role in nonadrenergic inhibitory responses in isolated human airways. J Appl Physiol (1985). 1986;61(4):1322–8.CrossRefGoogle Scholar
  76. 76.
    Ellis JL, Undem BJ. Inhibition by L-NG-nitro-L-arginine of nonadrenergic-noncholinergic-mediated relaxations of human isolated central and peripheral airway. Am Rev Respir Dis. 1992;146(6):1543–7.PubMedCrossRefGoogle Scholar
  77. 77.
    Mathioudakis A, Chatzimavridou-Grigoriadou V, Evangelopoulou E, Mathioudakis G. Vasoactive intestinal Peptide inhaled agonists: potential role in respiratory therapeutics. Hippokratia. 2013;17(1):12–6.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Regal JF, Johnson DE. Indomethacin alters the effects of substance-P and VIP on isolated airway smooth muscle. Peptides. 1983;4(4):581–4.PubMedCrossRefGoogle Scholar
  79. 79.
    Douglas JS, Duncan PG, Mukhopadhyay A. The antagonism of histamine-induced tracheal and bronchial muscle contraction by diphenhydramine: effect of maturation. Br J Pharmacol. 1984;83(3):697–705.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Persson GA, Ekman M. Contractile effects of histamine in large and small respiratory airways. Agents Actions. 1976;6(4):389–93.PubMedCrossRefGoogle Scholar
  81. 81.
    Perez JF, Sanderson MJ. The frequency of calcium oscillations induced by 5-HT, ACH, and KCl determine the contraction of smooth muscle cells of intrapulmonary bronchioles. J Gen Physiol. 2005;125(6):535–53.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Tran T, Stewart AG. Protease-activated receptor (PAR)-independent growth and pro-inflammatory actions of thrombin on human cultured airway smooth muscle. Br J Pharmacol. 2003;138(5):865–75.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Chambers LS, Black JL, Poronnik P, Johnson PR. Functional effects of protease-activated receptor-2 stimulation on human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2001;281(6):L1369–78.PubMedCrossRefGoogle Scholar
  84. 84.
    Cocks TM, Fong B, Chow JM, Anderson GP, Frauman AG, Goldie RG, et al. A protective role for protease-activated receptors in the airways. Nature. 1999;398(6723):156–60.PubMedCrossRefGoogle Scholar
  85. 85.
    Capra V, Thompson MD, Sala A, Cole DE, Folco G, Rovati GE. Cysteinyl-leukotrienes and their receptors in asthma and other inflammatory diseases: critical update and emerging trends. Med Res Rev. 2007;27(4):469–527.PubMedCrossRefGoogle Scholar
  86. 86.
    Mechiche H, Naline E, Candenas L, Pinto FM, Birembault P, Advenier C, et al. Effects of cysteinyl leukotrienes in small human bronchus and antagonist activity of montelukast and its metabolites. Clin Exp Allergy. 2003;33(7):887–94.PubMedCrossRefGoogle Scholar
  87. 87.
    Benyahia C, Gomez I, Kanyinda L, Boukais K, Danel C, Leseche G, et al. PGE(2) receptor (EP(4)) agonists: potent dilators of human bronchi and future asthma therapy? Pulm Pharmacol Ther. 2012;25(1):115–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Safholm J, Dahlen SE, Delin I, Maxey K, Stark K, Cardell LO, et al. PGE2 maintains the tone of the guinea pig trachea through a balance between activation of contractile EP1 receptors and relaxant EP2 receptors. Br J Pharmacol. 2013;168(4):794–806.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    FitzPatrick M, Donovan C, Bourke JE. Prostaglandin E2 elicits greater bronchodilation than salbutamol in mouse intrapulmonary airways in lung slices. Pulm Pharmacol Ther. 2014;28(1):68–76.PubMedCrossRefGoogle Scholar
  90. 90.
    Ressmeyer AR, Larsson AK, Vollmer E, Dahlen SE, Uhlig S, Martin C. Characterisation of guinea pig precision-cut lung slices: comparison with human tissues. Eur Respir J. 2006;28(3):603–11.PubMedCrossRefGoogle Scholar
  91. 91.
    Allen IC, Hartney JM, Coffman TM, Penn RB, Wess J, Koller BH. Thromboxane A2 induces airway constriction through an M3 muscarinic acetylcholine receptor-dependent mechanism. Am J Physiol Lung Cell Mol Physiol. 2006;290(3):L526–33.PubMedCrossRefGoogle Scholar
  92. 92.
    Goldie RG, Henry PJ, Knott PG, Self GJ, Luttmann MA, Hay DW. Endothelin-1 receptor density, distribution, and function in human isolated asthmatic airways. Am J Respir Crit Care Med. 1995;152(5 Pt 1):1653–8.PubMedCrossRefGoogle Scholar
  93. 93.
    Knott PG, Fernandes LB, Henry PJ, Goldie RG. Influence of endothelin-1 on cholinergic nerve-mediated contractions and acetylcholine release in rat isolated tracheal smooth muscle. J Pharmacol Exp Ther. 1996;279(3):1142–7.PubMedGoogle Scholar
  94. 94.
    Hay DW. Putative mediator role of endothelin-1 in asthma and other lung diseases. Clin Exp Pharmacol Physiol. 1999;26(2):168–71.PubMedCrossRefGoogle Scholar
  95. 95.
    Grunstein MM, Rosenberg SM, Schramm CM, Pawlowski NA. Mechanisms of action of endothelin 1 in maturing rabbit airway smooth muscle. Am J Phys. 1991;260(6 Pt 1):L434–43.Google Scholar
  96. 96.
    Gallos G, Townsend E, Yim P, Virag L, Zhang Y, Xu D, et al. Airway epithelium is a predominant source of endogenous airway GABA and contributes to relaxation of airway smooth muscle tone. Am J Physiol Lung Cell Mol Physiol. 2013;304(3):L191–7.PubMedCrossRefGoogle Scholar
  97. 97.
    Osawa Y, Xu D, Sternberg D, Sonett JR, D’Armiento J, Panettieri RA, et al. Functional expression of the GABAB receptor in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2006;291(5):L923–31.PubMedCrossRefGoogle Scholar
  98. 98.
    Mizuta K, Xu D, Pan Y, Comas G, Sonett JR, Zhang Y, et al. GABAA receptors are expressed and facilitate relaxation in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2008;294(6):L1206–16.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Gleason NR, Gallos G, Zhang Y, Emala CW. The GABAA agonist muscimol attenuates induced airway constriction in guinea pigs in vivo. J Appl Physiol (1985). 2009;106(4):1257–63.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Saxena H, Deshpande DA, Tiegs BC, Yan H, Battafarano RJ, Burrows WM, et al. The GPCR OGR1 (GPR68) mediates diverse signalling and contraction of airway smooth muscle in response to small reductions in extracellular pH. Br J Pharmacol. 2012;166(3):981–90.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Yarova PL, Stewart AL, Sathish V, Britt RD Jr, Thompson MA, Lowe APP, et al. Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Sci Transl Med. 2015;7(284):284ra60.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Pera T, Penn RB. Bronchoprotection and bronchorelaxation in asthma: new targets, and new ways to target the old ones. Pharmacol Ther. 2016;164:82–96.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Thirstrup S. Control of airway smooth muscle tone: II—pharmacology of relaxation. Respir Med. 2000;94(6):519–28.PubMedCrossRefGoogle Scholar
  104. 104.
    Thirstrup S. Control of airway smooth muscle tone. I—electrophysiology and contractile mediators. Respir Med. 2000;94(4):328–36.PubMedCrossRefGoogle Scholar
  105. 105.
    Kirkpatrick CT. Excitation and contraction in bovine tracheal smooth muscle. J Physiol. 1975;244(2):263–81.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Murray RK, Kotlikoff MI. Receptor-activated calcium influx in human airway smooth muscle cells. J Physiol. 1991;435:123–44.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Farley JM, Miles PR. The sources of calcium for acetylcholine-induced contractions of dog tracheal smooth muscle. J Pharmacol Exp Ther. 1978;207(2):340–6.PubMedGoogle Scholar
  108. 108.
    Liu X, Farley JM. Depletion and refilling of acetylcholine- and caffeine-sensitive Ca++ stores in tracheal myocytes. J Pharmacol Exp Ther. 1996;277(2):789–95.PubMedGoogle Scholar
  109. 109.
    Roux E, Guibert C, Savineau JP, Marthan R. [Ca2+]i oscillations induced by muscarinic stimulation in airway smooth muscle cells: receptor subtypes and correlation with the mechanical activity. Br J Pharmacol. 1997;120(7):1294–301.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Sanderson MJ, Delmotte P, Bai Y, Perez-Zogbhi JF. Regulation of airway smooth muscle cell contractility by Ca2+ signaling and sensitivity. Proc Am Thorac Soc. 2008;5(1):23–31.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Ressmeyer AR, Bai Y, Delmotte P, Uy KF, Thistlethwaite P, Fraire A, et al. Human airway contraction and formoterol-induced relaxation is determined by Ca2+ oscillations and Ca2+ sensitivity. Am J Respir Cell Mol Biol. 2010;43(2):179–91.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Bai Y, Sanderson MJ. The contribution of Ca2+ signaling and Ca2+ sensitivity to the regulation of airway smooth muscle contraction is different in rats and mice. Am J Physiol Lung Cell Mol Physiol. 2009;296(6):L947–58.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Wang YX, Zheng YM, Mei QB, Wang QS, Collier ML, Fleischer S, et al. FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells. Am J Physiol Cell Physiol. 2004;286(3):C538–46.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Du W, Stiber JA, Rosenberg PB, Meissner G, Eu JP. Ryanodine receptors in muscarinic receptor-mediated bronchoconstriction. J Biol Chem. 2005;280(28):26287–94.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Mahn K, Hirst SJ, Ying S, Holt MR, Lavender P, Ojo OO, et al. Diminished sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) expression contributes to airway remodelling in bronchial asthma. Proc Natl Acad Sci U S A. 2009;106(26):10775–80.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Bai Y, Edelmann M, Sanderson MJ. The contribution of inositol 1,4,5-trisphosphate and ryanodine receptors to agonist-induced Ca2+ signaling of airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2009;297(2):L347–L61.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Bergner A, Sanderson MJ. Acetylcholine-induced calcium signaling and contraction of airway smooth muscle cells in lung slices. J Gen Physiol. 2002;119(2):187–98.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Pelaia G, Renda T, Gallelli L, Vatrella A, Busceti MT, Agati S, et al. Molecular mechanisms underlying airway smooth muscle contraction and proliferation: implications for asthma. Respir Med. 2008;102(8):1173–81.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Deshpande DA, White TA, Dogan S, Walseth TF, Panettieri RA, Kannan MS. CD38/cyclic ADP-ribose signaling: role in the regulation of calcium homeostasis in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2005;288(5):L773–88.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Janssen LJ, Sims SM. Emptying and refilling of Ca2+ store in tracheal myocytes as indicated by ACh-evoked currents and contraction. Am J Phys. 1993;265(4 Pt 1):C877–86.CrossRefGoogle Scholar
  121. 121.
    Sathish V, Thompson MA, Bailey JP, Pabelick CM, Prakash YS, Sieck GC. Effect of proinflammatory cytokines on regulation of sarcoplasmic reticulum Ca2+ reuptake in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2009;297(1):L26–34.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Somlyo AP, Somlyo AV. Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev. 2003;83(4):1325–58.CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Gao N, Tsai MH, Chang AN, He W, Chen CP, Zhu M, et al. Physiological vs. pharmacological signalling to myosin phosphorylation in airway smooth muscle. J Physiol. 2017;595(19):6231–47.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Yoshii A, Iizuka K, Dobashi K, Horie T, Harada T, Nakazawa T, et al. Relaxation of contracted rabbit tracheal and human bronchial smooth muscle by Y-27632 through inhibition of Ca2+ sensitization. Am J Respir Cell Mol Biol. 1999;20(6):1190–200.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Mukherjee S, Trice J, Shinde P, Willis RE, Pressley TA, Perez-Zoghbi JF. Ca2+ oscillations, Ca2+ sensitization, and contraction activated by protein kinase C in small airway smooth muscle. J Gen Physiol. 2013;141(2):165–78.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Sparrow MP, Mitchell HW. Contraction of smooth muscle of pig airway tissues from before birth to maturity. J Appl Physiol (1985). 1990;68(2):468–77.CrossRefGoogle Scholar
  127. 127.
    Boie S, Chen J, Sanderson MJ, Sneyd J. The relative contributions of store-operated and voltage-gated Ca(2+) channels to the control of Ca(2+) oscillations in airway smooth muscle. J Physiol. 2017;595(10):3129–41.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Chen J, Sanderson MJ. Store-operated calcium entry is required for sustained contraction and Ca(2+) oscillations of airway smooth muscle. J Physiol. 2017;595(10):3203–18.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Peel SE, Liu B, Hall IP. ORAI and store-operated calcium influx in human airway smooth muscle cells. Am J Respir Cell Mol Biol. 2008;38(6):744–9.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Billington CK, Ojo OO, Penn RB, Ito S. cAMP regulation of airway smooth muscle function. Pulm Pharmacol Ther. 2013;26(1):112–20.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Morgan SJ, Deshpande DA, Tiegs BC, Misior AM, Yan H, Hershfeld AV, et al. beta-Agonist-mediated relaxation of airway smooth muscle is protein kinase A-dependent. J Biol Chem. 2014;289(33):23065–74.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Roscioni SS, Maarsingh H, Elzinga CR, Schuur J, Menzen M, Halayko AJ, et al. Epac as a novel effector of airway smooth muscle relaxation. J Cell Mol Med. 2011;15(7):1551–63.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Zieba BJ, Artamonov MV, Jin L, Momotani K, Ho R, Franke AS, et al. The cAMP-responsive Rap1 guanine nucleotide exchange factor, Epac, induces smooth muscle relaxation by down-regulation of RhoA activity. J Biol Chem. 2011;286(19):16681–92.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Nuttle LC, Farley JM. Frequency modulation of acetylcholine-induced oscillations in Ca++ and Ca(++)-activated Cl- current by cAMP in tracheal smooth muscle. J Pharmacol Exp Ther. 1996;277(2):753–60.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Delmotte P, Ressmeyer AR, Bai Y, Sanderson MJ. Mechanisms of airway smooth muscle relaxation induced by beta2-adrenergic agonists. Front Biosci (Landmark Ed). 2010;15:750–64.CrossRefGoogle Scholar
  136. 136.
    Perez-Zoghbi JF, Bai Y, Sanderson MJ. Nitric oxide induces airway smooth muscle cell relaxation by decreasing the frequency of agonist-induced Ca2+ oscillations. J Gen Physiol. 2010;135(3):247–59.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Oguma T, Kume H, Ito S, Takeda N, Honjo H, Kodama I, et al. Involvement of reduced sensitivity to Ca in beta-adrenergic action on airway smooth muscle. Clin Exp Allergy. 2006;36(2):183–91.PubMedCrossRefGoogle Scholar
  138. 138.
    Liu C, Zuo J, Janssen LJ. Regulation of airway smooth muscle RhoA/ROCK activities by cholinergic and bronchodilator stimuli. Eur Respir J. 2006;28(4):703–11.PubMedCrossRefGoogle Scholar
  139. 139.
    Kotlikoff MI, Kamm KE. Molecular mechanisms of beta-adrenergic relaxation of airway smooth muscle. Annu Rev Physiol. 1996;58:115–41.PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Torphy TJ, Undem BJ, Cieslinski LB, Luttmann MA, Reeves ML, Hay DW. Identification, characterization and functional role of phosphodiesterase isozymes in human airway smooth muscle. J Pharmacol Exp Ther. 1993;265(3):1213–23.PubMedGoogle Scholar
  141. 141.
    Billington CK, Le Jeune IR, Young KW, Hall IP. A major functional role for phosphodiesterase 4D5 in human airway smooth muscle cells. Am J Respir Cell Mol Biol. 2008;38(1):1–7.PubMedCrossRefGoogle Scholar
  142. 142.
    Holgate ST, Wenzel S, Postma DS, Weiss ST, Renz H, Sly PD. Asthma. Nat Rev Dis Primers. 2015;1:15025.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Barnes PJ, Burney PG, Silverman EK, Celli BR, Vestbo J, Wedzicha JA, et al. Chronic obstructive pulmonary disease. Nat Rev Dis Primers. 2015;1:15076.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Gosens R, Zaagsma J, Meurs H, Halayko AJ. Muscarinic receptor signaling in the pathophysiology of asthma and COPD. Respir Res. 2006;7:73.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    ten Berge RE, Zaagsma J, Roffel AF. Muscarinic inhibitory autoreceptors in different generations of human airways. Am J Respir Crit Care Med. 1996;154(1):43–9.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Hallstrand TS, Lai Y, Henderson WR Jr, Altemeier WA, Gelb MH. Epithelial regulation of eicosanoid production in asthma. Pulm Pharmacol Ther. 2012;25(6):432–7.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Wenzel SE, Larsen GL, Johnston K, Voelkel NF, Westcott JY. Elevated levels of leukotriene C4 in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge. Am Rev Respir Dis. 1990;142(1):112–9.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Fajt ML, Gelhaus SL, Freeman B, Uvalle CE, Trudeau JB, Holguin F, et al. Prostaglandin D(2) pathway upregulation: relation to asthma severity, control, and TH2 inflammation. J Allergy Clin Immunol. 2013;131(6):1504–12.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Fagan KA, McMurtry IF, Rodman DM. Role of endothelin-1 in lung disease. Respir Res. 2001;2(2):90–101.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Ackerman V, Carpi S, Bellini A, Vassalli G, Marini M, Mattoli S. Constitutive expression of endothelin in bronchial epithelial cells of patients with symptomatic and asymptomatic asthma and modulation by histamine and interleukin-1. J Allergy Clin Immunol. 1995;96(5 Pt 1):618–27.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Celik G, Karabiyikoglu G. Local and peripheral plasma endothelin-1 in pulmonary hypertension secondary to chronic obstructive pulmonary disease. Respiration. 1998;65(4):289–94.PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Lambert RK, Wiggs BR, Kuwano K, Hogg JC, Pare PD. Functional significance of increased airway smooth muscle in asthma and COPD. J Appl Physiol (1985). 1993;74(6):2771–81.CrossRefGoogle Scholar
  153. 153.
    O’Reilly M, Sozo F, Harding R. Impact of preterm birth and bronchopulmonary dysplasia on the developing lung: long-term consequences for respiratory health. Clin Exp Pharmacol Physiol. 2013;40(11):765–73.PubMedCrossRefGoogle Scholar
  154. 154.
    James AL, Bai TR, Mauad T, Abramson MJ, Dolhnikoff M, McKay KO, et al. Airway smooth muscle thickness in asthma is related to severity but not duration of asthma. Eur Respir J. 2009;34(5):1040–5.PubMedCrossRefGoogle Scholar
  155. 155.
    Benayoun L, Druilhe A, Dombret MC, Aubier M, Pretolani M. Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med. 2003;167(10):1360–8.PubMedCrossRefGoogle Scholar
  156. 156.
    Ward JE, Harris T, Bamford T, Mast A, Pain MC, Robertson C, et al. Proliferation is not increased in airway myofibroblasts isolated from asthmatics. Eur Respir J. 2008;32(2):362–71.PubMedCrossRefGoogle Scholar
  157. 157.
    Trian T, Benard G, Begueret H, Rossignol R, Girodet PO, Ghosh D, et al. Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J Exp Med. 2007;204(13):3173–81.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Roth M, Black JL. An imbalance in C/EBPs and increased mitochondrial activity in asthmatic airway smooth muscle cells: novel targets in asthma therapy? Br J Pharmacol. 2009;157(3):334–41.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Perry M, Baker J, Chung KF. Airway smooth muscle cells from patients with COPD exhibit a higher degree of cellular proliferation and steroid insensitivity than that from healthy patients. Eur Respir J. 2011;38(Suppl 55):748.Google Scholar
  160. 160.
    Michaeloudes C, Kuo CH, Haji G, Finch DK, Halayko AJ, Kirkham P, et al. Metabolic re-patterning in COPD airway smooth muscle cells. Eur Respir J. 2017;50(5):1700202.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Salter B, Pray C, Radford K, Martin JG, Nair P. Regulation of human airway smooth muscle cell migration and relevance to asthma. Respir Res. 2017;18(1):156.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Kanabar V, Simcock DE, Mahn K, O’Connor BJ, Hirst SJ. Airway smooth muscle migration is increased in asthmatics. Proc Am Thorac Soc. 2006;3:A280.Google Scholar
  163. 163.
    Johnson PR, Burgess JK, Ge Q, Poniris M, Boustany S, Twigg SM, et al. Connective tissue growth factor induces extracellular matrix in asthmatic airway smooth muscle. Am J Respir Crit Care Med. 2006;173(1):32–41.PubMedCrossRefGoogle Scholar
  164. 164.
    Al-Alawi M, Hassan T, Chotirmall SH. Transforming growth factor beta and severe asthma: a perfect storm. Respir Med. 2014;108(10):1409–23.PubMedCrossRefGoogle Scholar
  165. 165.
    Chan V, Burgess JK, Ratoff JC, O’Connor BJ, Greenough A, Lee TH, et al. Extracellular matrix regulates enhanced eotaxin expression in asthmatic airway smooth muscle cells. Am J Respir Crit Care Med. 2006;174(4):379–85.PubMedCrossRefGoogle Scholar
  166. 166.
    Johnson PR, Burgess JK, Underwood PA, Au W, Poniris MH, Tamm M, et al. Extracellular matrix proteins modulate asthmatic airway smooth muscle cell proliferation via an autocrine mechanism. J Allergy Clin Immunol. 2004;113(4):690–6.PubMedCrossRefGoogle Scholar
  167. 167.
    Parameswaran K, Radford K, Zuo J, Janssen LJ, O’Byrne PM, Cox PG. Extracellular matrix regulates human airway smooth muscle cell migration. Eur Respir J. 2004;24(4):545–51.PubMedCrossRefGoogle Scholar
  168. 168.
    Ghaffar O, Hamid Q, Renzi PM, Allakhverdi Z, Molet S, Hogg JC, et al. Constitutive and cytokine-stimulated expression of eotaxin by human airway smooth muscle cells. Am J Respir Crit Care Med. 1999;159(6):1933–42.PubMedCrossRefGoogle Scholar
  169. 169.
    Chen H, Tliba O, Van Besien CR, Panettieri RA Jr, Amrani Y. TNF-[alpha] modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KCl. J Appl Physiol (1985). 2003;95(2):864–72; discussion 3.CrossRefGoogle Scholar
  170. 170.
    Sukkar MB, Hughes JM, Armour CL, Johnson PR. Tumour necrosis factor-alpha potentiates contraction of human bronchus in vitro. Respirology. 2001;6(3):199–203.PubMedCrossRefGoogle Scholar
  171. 171.
    Cooper PR, Lamb R, Day ND, Branigan PJ, Kajekar R, San Mateo L, et al. TLR3 activation stimulates cytokine secretion without altering agonist-induced human small airway contraction or relaxation. Am J Physiol Lung Cell Mol Physiol. 2009;297(3):L530–7.PubMedCrossRefGoogle Scholar
  172. 172.
    Zhang Y, Adner M, Cardell LO. Up-regulation of bradykinin receptors in a murine in-vitro model of chronic airway inflammation. Eur J Pharmacol. 2004;489(1–2):117–26.PubMedCrossRefGoogle Scholar
  173. 173.
    Tliba O, Deshpande D, Chen H, Van Besien C, Kannan M, Panettieri RA Jr, et al. IL-13 enhances agonist-evoked calcium signals and contractile responses in airway smooth muscle. Br J Pharmacol. 2003;140(7):1159–62.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Jiang H, Xie Y, Abel PW, Toews ML, Townley RG, Casale TB, et al. Targeting phosphoinositide 3-kinase gamma in airway smooth muscle cells to suppress interleukin-13-induced mouse airway hyperresponsiveness. J Pharmacol Exp Ther. 2012;342(2):305–11.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Hirose K, Iwata A, Tamachi T, Nakajima H. Allergic airway inflammation: key players beyond the Th2 cell pathway. Immunol Rev. 2017;278(1):145–61.PubMedCrossRefGoogle Scholar
  176. 176.
    Kudo M, Melton AC, Chen C, Engler MB, Huang KE, Ren X, et al. IL-17A produced by alphabeta T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat Med. 2012;18(4):547–54.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, et al. Interleukin-13: central mediator of allergic asthma. Science. 1998;282(5397):2258–61.PubMedCrossRefGoogle Scholar
  178. 178.
    Renzetti LM, Paciorek PM, Tannu SA, Rinaldi NC, Tocker JE, Wasserman MA, et al. Pharmacological evidence for tumor necrosis factor as a mediator of allergic inflammation in the airways. J Pharmacol Exp Ther. 1996;278(2):847–53.PubMedGoogle Scholar
  179. 179.
    Thomas PS, Heywood G. Effects of inhaled tumour necrosis factor alpha in subjects with mild asthma. Thorax. 2002;57(9):774–8.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Amrani Y. TNF-alpha and calcium signaling in airway smooth muscle cells: a never-ending story with promising therapeutic relevance. Am J Respir Cell Mol Biol. 2007;36(3):387–8.PubMedCrossRefGoogle Scholar
  181. 181.
    Risse PA, Jo T, Suarez F, Hirota N, Tolloczko B, Ferraro P, et al. Interleukin-13 inhibits proliferation and enhances contractility of human airway smooth muscle cells without change in contractile phenotype. Am J Physiol Lung Cell Mol Physiol. 2011;300(6):L958–66.PubMedCrossRefGoogle Scholar
  182. 182.
    Jude JA, Solway J, Panettieri RA Jr, Walseth TF, Kannan MS. Differential induction of CD38 expression by TNF-{alpha} in asthmatic airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2010;299(6):L879–90.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Mahn K, Ojo OO, Chadwick G, Aaronson PI, Ward JP, Lee TH. Ca(2+) homeostasis and structural and functional remodelling of airway smooth muscle in asthma. Thorax. 2010;65(6):547–52.PubMedCrossRefGoogle Scholar
  184. 184.
    Sweeney D, Hollins F, Gomez E, Mistry R, Saunders R, Challiss RA, et al. No evidence for altered intracellular calcium-handling in airway smooth muscle cells from human subjects with asthma. BMC Pulm Med. 2015;15:12.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Kellner J, Tantzscher J, Oelmez H, Edelmann M, Fischer R, Huber RM, et al. Mechanisms altering airway smooth muscle cell Ca+ homeostasis in two asthma models. Respiration. 2008;76(2):205–15.PubMedCrossRefGoogle Scholar
  186. 186.
    Tao FC, Tolloczko B, Mitchell CA, Powell WS, Martin JG. Inositol (1,4,5)trisphosphate metabolism and enhanced calcium mobilization in airway smooth muscle of hyperresponsive rats. Am J Respir Cell Mol Biol. 2000;23(4):514–20.PubMedCrossRefGoogle Scholar
  187. 187.
    Du Y, Zhao J, Li X, Jin S, Ma WL, Mu Q, et al. Dissociation of FK506-binding protein 12.6 kD from ryanodine receptor in bronchial smooth muscle cells in airway hyperresponsiveness in asthma. Am J Respir Cell Mol Biol. 2014;50(2):398–408.PubMedPubMedCentralGoogle Scholar
  188. 188.
    Jain D, Keslacy S, Tliba O, Cao Y, Kierstein S, Amin K, et al. Essential role of IFNbeta and CD38 in TNFalpha-induced airway smooth muscle hyper-responsiveness. Immunobiology. 2008;213(6):499–509.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Croisier H, Tan X, Chen J, Sneyd J, Sanderson MJ, Brook BS. Ryanodine receptor sensitization results in abnormal calcium signaling in airway smooth muscle cells. Am J Respir Cell Mol Biol. 2015;53(5):703–11.PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Sakai H, Suto W, Kai Y, Chiba Y. Mechanisms underlying the pathogenesis of hyper-contractility of bronchial smooth muscle in allergic asthma. J Smooth Muscle Res. 2017;53(0):37–47.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Hunter I, Cobban HJ, Vandenabeele P, MacEwan DJ, Nixon GF. Tumor necrosis factor-alpha-induced activation of RhoA in airway smooth muscle cells: role in the Ca2+ sensitization of myosin light chain20 phosphorylation. Mol Pharmacol. 2003;63(3):714–21.PubMedCrossRefGoogle Scholar
  192. 192.
    Donovan C, Royce SG, Esposito J, Tran J, Ibrahim ZA, Tang ML, et al. Differential effects of allergen challenge on large and small airway reactivity in mice. PLoS One. 2013;8(9):e74101.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Ma X, Cheng Z, Kong H, Wang Y, Unruh H, Stephens NL, et al. Changes in biophysical and biochemical properties of single bronchial smooth muscle cells from asthmatic subjects. Am J Physiol Lung Cell Mol Physiol. 2002;283(6):L1181–9.PubMedCrossRefGoogle Scholar
  194. 194.
    Matsumoto H, Moir LM, Oliver BG, Burgess JK, Roth M, Black JL, et al. Comparison of gel contraction mediated by airway smooth muscle cells from patients with and without asthma. Thorax. 2007;62(10):848–54.PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Sutcliffe A, Hollins F, Gomez E, Saunders R, Doe C, Cooke M, et al. Increased nicotinamide adenine dinucleotide phosphate oxidase 4 expression mediates intrinsic airway smooth muscle hypercontractility in asthma. Am J Respir Crit Care Med. 2012;185(3):267–74.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Wang CG, Almirall JJ, Dolman CS, Dandurand RJ, Eidelman DH. In vitro bronchial responsiveness in two highly inbred rat strains. J Appl Physiol (1985). 1997;82(5):1445–52.PubMedCrossRefGoogle Scholar
  197. 197.
    Mitchell RW, Ruhlmann E, Magnussen H, Leff AR, Rabe KF. Passive sensitization of human bronchi augments smooth muscle shortening velocity and capacity. Am J Phys. 1994;267(2 Pt 1):L218–22.Google Scholar
  198. 198.
    Leguillette R, Laviolette M, Bergeron C, Zitouni N, Kogut P, Solway J, et al. Myosin, transgelin, and myosin light chain kinase: expression and function in asthma. Am J Respir Crit Care Med. 2009;179(3):194–204.PubMedCrossRefGoogle Scholar
  199. 199.
    Peters SP, Jones CA, Haselkorn T, Mink DR, Valacer DJ, Weiss ST. Real-world Evaluation of Asthma Control and Treatment (REACT): findings from a national Web-based survey. J Allergy Clin Immunol. 2007;119(6):1454–61.PubMedCrossRefGoogle Scholar
  200. 200.
    Lemoine H, Overlack C. Highly potent beta-2 sympathomimetics convert to less potent partial agonists as relaxants of guinea pig tracheae maximally contracted by carbachol. Comparison of relaxation with receptor binding and adenylate cyclase stimulation. J Pharmacol Exp Ther. 1992;261(1):258–70.PubMedGoogle Scholar
  201. 201.
    Trian T, Burgess JK, Niimi K, Moir LM, Ge Q, Berger P, et al. beta2-Agonist induced cAMP is decreased in asthmatic airway smooth muscle due to increased PDE4D. PLoS One. 2011;6(5):e20000.PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Deshpande DA, Theriot BS, Penn RB, Walker JK. Beta-arrestins specifically constrain beta2-adrenergic receptor signaling and function in airway smooth muscle. FASEB J. 2008;22(7):2134–41.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Pera T, Hegde A, Deshpande DA, Morgan SJ, Tiegs BC, Theriot BS, et al. Specificity of arrestin subtypes in regulating airway smooth muscle G protein-coupled receptor signaling and function. FASEB J. 2015;29(10):4227–35.PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Gupta MK, Asosingh K, Aronica M, Comhair S, Cao G, Erzurum S, et al. Defective resensitization in human airway smooth muscle cells evokes beta-adrenergic receptor dysfunction in severe asthma. PLoS One. 2015;10(5):e0125803.PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM, Group SS. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006;129(1):15–26.PubMedCrossRefGoogle Scholar
  206. 206.
    Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med. 2006;144(12):904–12.PubMedCrossRefGoogle Scholar
  207. 207.
    Laporte JC, Moore PE, Baraldo S, Jouvin MH, Church TL, Schwartzman IN, et al. Direct effects of interleukin-13 on signaling pathways for physiological responses in cultured human airway smooth muscle cells. Am J Respir Crit Care Med. 2001;164(1):141–8.PubMedCrossRefGoogle Scholar
  208. 208.
    Guo M, Pascual RM, Wang S, Fontana MF, Valancius CA, Panettieri RA Jr, et al. Cytokines regulate beta-2-adrenergic receptor responsiveness in airway smooth muscle via multiple PKA- and EP2 receptor-dependent mechanisms. Biochemistry. 2005;44(42):13771–82.PubMedCrossRefGoogle Scholar
  209. 209.
    Shore SA, Laporte J, Hall IP, Hardy E, Panettieri RAJ. Effect of IL-1 beta on responses of cultured human airway smooth muscle cells to bronchodilator agonists. Am J Respir Cell Mol Biol. 1997;16(6):702–12.PubMedCrossRefGoogle Scholar
  210. 210.
    Darveaux J, Busse WW. Biologics in asthma—the next step toward personalized treatment. J Allergy Clin Immunol Pract. 2015;3(2):152–60; quiz 61PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Yousuf A, Brightling CE. Biologic drugs: a new target therapy in COPD? COPD. 2018;15(2):99–107.PubMedCrossRefGoogle Scholar
  212. 212.
    Ntontsi P, Papathanassiou E, Loukides S, Bakakos P, Hillas G. Targeted anti-IL-13 therapies in asthma: current data and future perspectives. Expert Opin Investig Drugs. 2018;27(2):179–86.PubMedCrossRefGoogle Scholar
  213. 213.
    Schmidt DT, Watson N, Dent G, Ruhlmann E, Branscheid D, Magnussen H, et al. The effect of selective and non-selective phosphodiesterase inhibitors on allergen- and leukotriene C(4)-induced contractions in passively sensitized human airways. Br J Pharmacol. 2000;131(8):1607–18.PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Wedzicha JA, Calverley PM, Rabe KF. Roflumilast: a review of its use in the treatment of COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:81–90.PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Deshpande DA, Robinett KS, Wang WC, Sham JS, An SS, Liggett SB. Bronchodilator activity of bitter tastants in human tissue. Nat Med. 2011;17(7):776–8.PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Deshpande DA, Wang WC, McIlmoyle EL, Robinett KS, Schillinger RM, An SS, et al. Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nat Med. 2010;16(11):1299–304.PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Tan X, Sanderson MJ. Bitter tasting compounds dilate airways by inhibiting airway smooth muscle calcium oscillations and calcium sensitivity. Br J Pharmacol. 2014;171(3):646–62.PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Robinett KS, Koziol-White CJ, Akoluk A, An SS, Panettieri RA Jr, Liggett SB. Bitter taste receptor function in asthmatic and nonasthmatic human airway smooth muscle cells. Am J Respir Cell Mol Biol. 2014;50(4):678–83.PubMedPubMedCentralCrossRefGoogle Scholar
  219. 219.
    An SS, Wang WC, Koziol-White CJ, Ahn K, Lee DY, Kurten RC, et al. TAS2R activation promotes airway smooth muscle relaxation despite beta(2)-adrenergic receptor tachyphylaxis. Am J Physiol Lung Cell Mol Physiol. 2012;303(4):L304–11.PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Lam M, Royce SG, Samuel CS, Bourke JE. Serelaxin as a novel therapeutic opposing fibrosis and contraction in lung diseases. Pharmacol Ther. 2018;187:61–70.PubMedCrossRefGoogle Scholar
  221. 221.
    Pini A, Boccalini G, Lucarini L, Catarinicchia S, Guasti D, Masini E, et al. Protection from cigarette smoke-induced lung dysfunction and damage by H2 relaxin (Serelaxin). J Pharmacol Exp Ther. 2016;357(3):451–8.PubMedCrossRefGoogle Scholar
  222. 222.
    Bani D, Ballati L, Masini E, Bigazzi M, Sacchi TB. Relaxin counteracts asthma-like reaction induced by inhaled antigen in sensitized guinea pigs. Endocrinology. 1997;138(5):1909–15.PubMedCrossRefGoogle Scholar
  223. 223.
    Lam M, Royce SG, Donovan C, Jelinic M, Parry LJ, Samuel CS, et al. Serelaxin elicits bronchodilation and enhances beta-adrenoceptor-mediated airway relaxation. Front Pharmacol. 2016;7:406.PubMedPubMedCentralCrossRefGoogle Scholar
  224. 224.
    Diez J. Serelaxin: a novel therapy for acute heart failure with a range of hemodynamic and non-hemodynamic actions. Am J Cardiovasc Drugs. 2014;14(4):275–85.PubMedPubMedCentralCrossRefGoogle Scholar
  225. 225.
    Matthey M, Roberts R, Seidinger A, Simon A, Schroder R, Kuschak M, et al. Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma. Sci Transl Med. 2017;9(407):eaag2288.PubMedCrossRefGoogle Scholar
  226. 226.
    Yin LM, Xu YD, Peng LL, Duan TT, Liu JY, Xu Z, et al. Transgelin-2 as a therapeutic target for asthmatic pulmonary resistance. Sci Transl Med. 2018;10(427):eaam8604.PubMedPubMedCentralCrossRefGoogle Scholar
  227. 227.
    Cox PG, Miller J, Mitzner W, Leff AR. Radiofrequency ablation of airway smooth muscle for sustained treatment of asthma: preliminary investigations. Eur Respir J. 2004;24(4):659–63.PubMedCrossRefGoogle Scholar
  228. 228.
    d’Hooghe JNS, Ten Hacken NHT, Weersink EJM, Sterk PJ, Annema JT, Bonta PI. Emerging understanding of the mechanism of action of bronchial thermoplasty in asthma. Pharmacol Ther. 2018;181:101–7.PubMedCrossRefGoogle Scholar
  229. 229.
    Thomson NC, Chanez P. How effective is bronchial thermoplasty for severe asthma in clinical practice? Eur Respir J. 2017;50(2):1701140.PubMedCrossRefGoogle Scholar
  230. 230.
    Pretolani M, Bergqvist A, Thabut G, Dombret MC, Knapp D, Hamidi F, et al. Effectiveness of bronchial thermoplasty in patients with severe refractory asthma: clinical and histopathologic correlations. J Allergy Clin Immunol. 2017;139(4):1176–85.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of PharmacologyBiomedicine Discovery Institute, Monash UniversityClaytonAustralia

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