Current Allergy and Asthma Reports

, Volume 4, Issue 2, pp 109–115 | Cite as

Factors controlling airway smooth muscle proliferation in asthma

  • Alastair G. Stewart
  • John V. Bonacci
  • Lilly Quan
Article

Abstract

Airway smooth muscle proliferation has been the focus of considerable attention, as it is a quantitatively important component of the airway wall remodeling response in asthma and has been suggested as a suitable target for the development of novel anti-asthma agents. Such agents are considered likely to reduce airway hyperresponsiveness and, consequently, airway obstruction, resulting in fewer symptoms and exacerbations. Identifying suitable drug targets has proved an elusive goal, as no dominant molecular mechanism for remodeling has emerged. Moreover, recent findings raise some doubt as to whether smooth muscle proliferation per se is the explanation of the increase in smooth muscle cell number in asthma, with alternative explanations including the proposal that cells migrate either from the interstitial compartment or from a circulating precursor stem cell population. Therefore, drug targeting of migration responses should be considered as an alternative approach to regulating the smooth muscle component of airway wall remodeling.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Huber HL, Koessler KK: The pathology of bronchial asthma. Arch Intern Med 1922, 30:689–760.Google Scholar
  2. 2.
    Dunnill MS, Massarella GR: A comparison of the quantitative anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis, and in emphysema. Thorax 1969, 24:176–179.PubMedGoogle Scholar
  3. 3.
    James AL, Pare PD, Hogg JC: The mechanics of airway narrowing in asthma. Am Rev Respir Dis 1989, 139:242–246.PubMedGoogle Scholar
  4. 4.
    Wiggs BR, Moreno R, Hogg JC, et al.: A model of the mechanics of airway narrowing. J Appl Physiol 1990, 69:849–860.PubMedGoogle Scholar
  5. 5.
    Pare PD, Wiggs BR, James A, et al.: The comparative mechanics and morphology of airways in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 1991, 143:1189–1193.PubMedGoogle Scholar
  6. 6.
    Wiggs BR, Bosken C, Pare D, et al.: A model of airway narrowing in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 1992, 145:1251–1258.PubMedGoogle Scholar
  7. 7.
    Lambert RK, Wiggs BR, Kuwano K, et al.: Functional significance of increased airway smooth muscle in asthma and COPD. J Appl Physiol 1993, 74:2771–2781.PubMedCrossRefGoogle Scholar
  8. 8.
    Lambert RK, Pare PD, Seow CY, et al.: Functional significance of increased airway smooth muscle in asthma and COPD. J Appl Physiol 1993, 74:2771–2781.PubMedCrossRefGoogle Scholar
  9. 9.
    Stewart AG, Tomlinson PR, Wilson J: Airway wall remodelling in asthma: a novel target for the development of anti-asthma drugs. Trends Pharmacol Sci 1993, 14:275–279.PubMedCrossRefGoogle Scholar
  10. 10.
    Halayko AJ, Solway J: Molecular mechanisms of phenotypic plasticity in smooth muscle cells. J Appl Physiol 2001, 90:358–368.PubMedGoogle Scholar
  11. 11.
    Moir LM, Leung SY, Eynott PR, et al.: Repeated allergen inhalation induces phenotypic modulation of smooth muscle in bronchioles of sensitized rats. Am J Physiol Lung Cell Mol Physiol 2003, 284:L148-L159.PubMedGoogle Scholar
  12. 12.
    Jiang H, Zhu Y, Wang X, Shu YS: Increased Ca2+ and myosin phosphorylation, but not calmodulin activity in sensitized airway smooth muscles. Am J Physiol 1995, 268:L739-L746.PubMedGoogle Scholar
  13. 13.
    Ma X, Cheng Z, Kong H, 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:L1181-L1189. This study in biopsy-isolated ASM cells shows an intrinsic increase in contractility, as measured by velocity of shortening rather than equilibrium tension development.PubMedGoogle Scholar
  14. 14.
    Ma X, Wang Y, Stephens NL: Serum deprivation induces a unique hypercontractile phenotype of cultured smooth muscle cells. Am J Physiol 1998, 274:C1206-C1214.PubMedGoogle Scholar
  15. 15.
    Amrani Y, Krymskaya V, Maki C, Panettieri RA Jr:: Mechanisms underlying TNF-alpha effects on agonist-mediated calcium homeostasis in human airway smooth muscle cells. Am J Physiol 1997, 273:L1020-L1028.PubMedGoogle Scholar
  16. 16.
    Pare PD, Bai TR: The consequences of chronic allergic inflammation. Thorax 1995, 50:328–332.PubMedCrossRefGoogle Scholar
  17. 17.
    Fernandes DJ, Mitchell RW, Lasker O, et al.: Do inflammatory mediators influence the contribution of airway smooth muscle contraction to airway hyperresponsiveness in asthma? J Appl Physiol 2003, 95:844–853.PubMedGoogle Scholar
  18. 18.
    Deshpande DA, Walseth TF, Panettieri RA, Kannan MS: CD38/ cyclic ADP-ribose-mediated Ca2+ signaling contributes to airway smooth muscle hyper-responsiveness. FASEB J 2003, 17:452–454.PubMedGoogle Scholar
  19. 19.
    Leuppi JD, Salome CM, Jenkins CR, et al.: Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med 2001, 163:406–412.PubMedGoogle Scholar
  20. 20.
    Boulet LP: Asymptomatic airway hyperresponsiveness: a curiosity or an opportunity to prevent asthma? Am J Respir Crit Care Med 2003, 167:371–378.PubMedCrossRefGoogle Scholar
  21. 21.
    Holtzman MJ: Drug development for asthma. Am J Respir Cell Mol Biol 2003, 29:163–171.PubMedCrossRefGoogle Scholar
  22. 22.
    James AL, Maxwell PS, Pearce-Pinto G, et al.: The relationship of reticular basement membrane thickness to airway wall remodeling in asthma. Am J Respir Crit Care Med 2002, 166:1590–1595.PubMedCrossRefGoogle Scholar
  23. 23.
    Chu HW, Halliday JL, Martin RJ, et al.: Collagen deposition in large airways may not differentiate severe asthma from milder forms of the disease. Am J Respir Crit Care Med 1998, 158:1936–1944.PubMedGoogle Scholar
  24. 24.
    Payne DN, Rogers AV, Adelroth E, et al.: Early thickening of the reticular basement membrane in children with difficult asthma. Am J Respir Crit Care Med 2003, 167:78–82.PubMedCrossRefGoogle Scholar
  25. 25.
    Jenkins HA, Cool C, Szefler SJ, et al.: Histopathology of severe childhood asthma: a case series. Chest 2003, 124:32–41.PubMedCrossRefGoogle Scholar
  26. 26.
    Benayoun L, Druilhe A, Dombret MC, et al.: Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med 2003, 167:1360–1368.PubMedCrossRefGoogle Scholar
  27. 27.
    Martin JG, Ramos-Barbon D: Airway smooth muscle growth from the perspective of animal models. Respir Physiol Neurobiol 2003, 137:251–261.PubMedCrossRefGoogle Scholar
  28. 28.
    Vanacker NJ, Palmans E, Pauwel RA, Kips JC: Fluticasone inhibits the progression of allergen-induced structural airway changes. Clin Exp Allergy 2002, 32:914–920.PubMedCrossRefGoogle Scholar
  29. 29.
    Vanacker NJ, Palmans E, Kips JC Pauwel RA: Fluticasone inhibits but does not reverse allergen-induced structural airway changes. Am J Respir Crit Care Med 2001, 163:674–679.PubMedGoogle Scholar
  30. 30.
    Salmon M, Walsh DA, Huang TJ, et al.: Involvement of cysteinyl leukotrienes in airway smooth muscle cell DNA synthesis after repeated allergen exposure in sensitized Brown Norway rats. Br J Pharmacol 1999, 127:1151–1158.PubMedCrossRefGoogle Scholar
  31. 31.
    Hirst SJ: Airway smooth muscle as a target in asthma. Clin Exp Allergy 2000, 30(Suppl1):54–59.PubMedCrossRefGoogle Scholar
  32. 32.
    Stewart AG: Airway wall remodelling and hyperresponsiveness: modelling remodelling in vitro and in vivo. Pulm Pharmacol Ther 2001, 14:255–265.PubMedCrossRefGoogle Scholar
  33. 33.
    Thomson RJ, Bramley AM, Schellenberg RR: Airway muscle stereology: implications for increased shortening in asthma. Am J Respir Crit Care Med 1996, 154:749–757.PubMedGoogle Scholar
  34. 34.
    Ravenhall CE, Guida E, Harris T, et al.: The importance of ERK activity in the regulation of cyclin D1 levels and DNA synthesis in human cultured airway smooth muscle. Br J Pharmacol 2000, 131:17–28.PubMedCrossRefGoogle Scholar
  35. 35.
    Krymskaya VP, Penn RB, Osini MJ: Phosphatidylinositol 3-kinase mediates mitogen-induced human airway smooth muscle cell proliferation. Am J Physiol 1999, 277:L65-L78.PubMedGoogle Scholar
  36. 36.
    Goncharova EA, Goncharov DA, Eszterhas A, et al.: Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation: a role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem 2002, 277:30958–30967.PubMedCrossRefGoogle Scholar
  37. 37.
    Fernandes DJ, Ravenhall CE, Harris T, et al.: Contribution of the p38mapk signalling pathway to proliferation in human cultured airway smooth muscle cells is mitogen-specific. Br J Pharmacol 2004, In press.Google Scholar
  38. 38.
    Zacour ME, Martin JG: Enhanced growth response of airway smooth muscle in inbred rats with airway hyperresponsiveness. Am J Respir Cell Mol Biol 1996, 15:590–599.PubMedGoogle Scholar
  39. 39.
    Johnson PR, Roth M, Tamm M, et al.: Airway smooth muscle cell proliferation is increased in asthma. Am J Respir Crit Care Med 2001, 164:474–477. An inherent increase in the proliferative response of asthmatic airway smooth muscle is described for the first time.PubMedGoogle Scholar
  40. 40.
    Freyer AM, Johnson SR, Hall IP: Effects of growth factors and extracellular matrix on survival of human airway smooth muscle cells. Am J Respir Cell Mol Biol 2001, 25:569–576.PubMedGoogle Scholar
  41. 41.
    Zhou D, Zheng X, Wang L, et al.: Expression and effects of cardiotrophin-1 (CT-1) in human airway smooth muscle cells. Br J Pharmacol 2003, 140:1237–1244.PubMedCrossRefGoogle Scholar
  42. 42.
    Campbell JH, Rennick RE, Kalevitch SG, Campbell GR: Heparan sulfate-degrading enzymes induce modulation of smooth muscle phenotype. Exp Cell Res 1992, 200:156–167.PubMedCrossRefGoogle Scholar
  43. 43.
    Johnson PR, Armour CL, Carey D, Black JL: Heparin and PGE2 inhibit DNA synthesis in human airway smooth muscle cells in culture. Am J Physiol 1995, 269:L514-L519.PubMedGoogle Scholar
  44. 44.
    Hirst SJ, Twort CH, Lee TH: Differential effects of extracellular matrix proteins on human airway smooth muscle cell proliferation and phenotype. Am J Respir Cell Mol Biol 2000, 23:335–344.PubMedGoogle Scholar
  45. 45.
    Bonacci JV, Harris T, Wilson JW, Stewart AG: Collagen-induced resistance to glucocorticoid anti-mitogenic actions: a potential explanation of smooth muscle hyperplasia in the asthmatic remodelled airway. Br J Pharmacol 2003, 138:1203–1206. These findings suggest that the pathologic extracellular matrix found in the asthmatic remodeled airway influences the pharmacology of anti-asthma agents.PubMedCrossRefGoogle Scholar
  46. 46.
    Stewart AG: Airway smooth muscle as a target for novel antiasthma drugs acting on airway wall remodeling. In Airway Wall Remodelling. Edited by Howarth P, Wilson JW, Bousquet J,et al. New York: Marcel Dekker; 2001:217–243.Google Scholar
  47. 47.
    Gizycki MJ, Adelroth E, Rogers AV, et al.: Myofibroblast involvement in the allergen-induced late response in mild atopic asthma. Am J Respir Cell Mol Biol 1997, 16:664–673.PubMedGoogle Scholar
  48. 48.
    Schmidt M, Sun G, Stacey MA, et al.: Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 2003, 171:380–389. An alternative explanation for increased numbers of myofibroblasts and airway smooth muscle cells is provided in this study in mice and in human asthmatics.PubMedGoogle Scholar
  49. 49.
    Stewart AG, Tomlinson PR, Wilson JW: Regulation of airway wall remodeling: prospects for the development of novel antiasthma drugs. Adv Pharmacol 1995, 33:209–253.PubMedCrossRefGoogle Scholar
  50. 50.
    Hughes RA, Harris T, Altmann E, et al.: 2-Methoxyestradiol and analogs as novel antiproliferative agents: analysis of threedimensional quantitative structure-activity relationships for DNA synthesis inhibition and estrogen receptor binding. Mol Pharmacol 2002, 61:1053–1069.PubMedCrossRefGoogle Scholar
  51. 51.
    Stewart AG, Vlahos R, Fernandes DJ, Hughes RA: Oestradiol metabolites: effects on airway wall remodelling. In New Drugs for Asthma, Allergy and COPD: Progress in Respiration Research, vol 31. Edited by Hansel TT, Barnes PJ. Basel: Karger; 2001.Google Scholar
  52. 52.
    Dashtaki R, Whorton AR, Murphy TM, et al.: Dehydroepiandrosterone and analogs inhibit DNA binding of AP-1 and airway smooth muscle proliferation. J Pharmacol Exp Ther 1998, 285:876–883.PubMedGoogle Scholar
  53. 53.
    Stewart AG, Tomlinson PR, Fernandes DJ: Tumor necrosis factor alpha modulates mitogenic responses of human cultured airway smooth muscle. Am J Respir Cell Mol Biol 1995, 12:110–119.PubMedGoogle Scholar
  54. 54.
    Amrani Y, Tliba O, Choubey D, et al.: IFN-gamma inhibits human airway smooth muscle cell proliferation by modulating the E2F-1/Rb pathway. Am J Physiol Lung Cell Mol Physiol 2003, 284:L1063-L1071.PubMedGoogle Scholar
  55. 55.
    Lazaar AL, Plotnick MI, Kucich U, et al.: Mast cell chymase modifies cell-matrix interactions and inhibits mitogeninduced proliferation of human airway smooth muscle cells. J Immunol 2002, 169:1014–1020.PubMedGoogle Scholar
  56. 56.
    Brightling CE, Bradding P, Symon FA, et al.: Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002, 346:1699–1705. This work establishes the potential for mast cells to play a central role in regulating ASM contribution to remodeling.PubMedCrossRefGoogle Scholar
  57. 57.
    Roth M, Johnson PR, Rudiger JJ, et al.: Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet 2002, 360:1293–1299.PubMedCrossRefGoogle Scholar
  58. 58.
    Fernandes D, Guida E, Koutsoubos V, et al.: Glucocorticoids inhibit proliferation, cyclin D1 expression and retinoblastoma protein phosphorylation, but not activity of the extracellular regulated kinases (ERK) in human cultured airway smooth muscle. Am J Respir Cell Mol Biol 1999, 21:77–88.PubMedGoogle Scholar
  59. 59.
    Goncharova EA, Billington CK, Irani C, et al.: Cyclic AMPmobilizing agents and glucocorticoids modulate human smooth muscle cell migration. Am J Respir Cell Mol Biol 2003, 29:19–27. The findings indicate that beta2-adrenoreceptor agonists and glucocorticoids might regulate mesenchymal cell migration in the pathogenesis of airway-wall remodeling.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2004

Authors and Affiliations

  • Alastair G. Stewart
    • 1
  • John V. Bonacci
    • 1
  • Lilly Quan
    • 1
  1. 1.Department of PharmacologyUniversity of MelbourneVictoriaAustralia

Personalised recommendations