Clinical Reviews in Allergy & Immunology

, Volume 24, Issue 1, pp 73–84 | Cite as

What evidence implicates airway smooth muscle in the cause of BHR?

  • Nickolai O. Dulin
  • Darren J. Fernandes
  • Maria Dowell
  • Shashi Bellam
  • John McConville
  • Oren Lakser
  • Richard Mitchell
  • Blanca Camoretti-Mercado
  • Paul Kogut
  • Julian SolwayEmail author


Bronchial hyperresponsiveness (BHR), the occurrence of excessive bronchoconstriction in response to relatively small constrictor stimuli, is a cardinal feature of asthma. Here, we consider the role that airway smooth muscle might play in the generation of BHR. The weight of evidence suggests that smooth muscle isolated from asthmatic tissues exhibits normal sensitivity to constrictor agonists when studied during isometric contraction, but the increased muscle mass within asthmatic airways might generate more total force than the lesser amount of muscle found in normal bronchi. Another salient difference between asthmatic and normal individuals lies in the effect of deep inhalation (DI) on bronchoconstriction. DI often substantially reverses induced bronchoconstriction in normals, while it often has much less effect on spontaneous or induced bronchoconstriction in asthmatics. It has been proposed that abnormal dynamic aspects of airway smooth muscle contraction—velocity of contraction or plasticity-elasticity balance—might underlie the abnormal DI response in asthma. We suggest a speculative model in which abnormally long actin filaments might account for abnormally increased elasticity of contracted airway smooth muscle.

Index Entries

Asthma deep breath inhalation actin hyperresponsive 


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  1. 1.
    Pare, P. D., et al. (1991). The comparative mechaniscs and morphology of airways in asthma and in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 143(5 Pt. 1), 1189–1193.PubMedGoogle Scholar
  2. 2.
    Wiggs, B. R., et al. (1992). A model of airway narrowing in asthma and in chronic obstructivepulmonary disease. Am. Rev. Respir. Dis. 145(6), 1251–1258.PubMedGoogle Scholar
  3. 3.
    Lambert, R. K., et al. (1993). Functional significance of increased airway smooth muscle in asthma and COPD. J. Appl. Physiol. 74(6), 2771–2781.PubMedGoogle Scholar
  4. 4.
    Pare, P. D., et al. (1997). The functional consequences of airway remodeling in asthma. Monaldi Arch. Chest Dis. 52(6), 589–596.PubMedGoogle Scholar
  5. 5.
    Woolcock, A. J., et al. (1991). Characteristics of bronchial hyperresponsiveness in chronic obstructive pulmonary disease and in asthma. Am. Rev. Respir. Dis. 143(6), 1438–1443.PubMedGoogle Scholar
  6. 6.
    Fish, J. E., et al. (1981). Regulation of bronchomotor tone by lung inflation in asthmatic and nonasthmatic subjects. J. Appl. Physiol. 50(5), 1079–1086PubMedGoogle Scholar
  7. 7.
    de Jongste, J. C., et al. (1987). In vitro responses of airways from an asthamtic patients. Eur. J. Respir. Dis. 71(1), 23–29.PubMedGoogle Scholar
  8. 8.
    Schellenberg, R. R. and Foster, A. (1984), In vitro responses of human asthmatic airway and pulmonary vascular smooth muscle. Int. Arch. Allergy Appl. Immunol. 75(3), 237–241.PubMedGoogle Scholar
  9. 9.
    Bjorck, T., Gustafsson, L. E., and Dahlen, S. E. (1992), Isolated bronchi from asthmatics are hyperresponsive to adenosine, which apparently acts indirectly by liberation of leukotrienes and histamine. Am. Rev. Respir. Dis. 145(5), 1087–1091.PubMedGoogle Scholar
  10. 10.
    Thomson, N. C. (1987). In vivo versus in vitro human airway responsiveness to different pharmacologic stimuli. Am. Rev. Respir. Dis. 136(4 Pt. 2), S58-S62.PubMedGoogle Scholar
  11. 11.
    Black, J. L. (1996). Role of airway smooth muscle. Am. J. Respir. Crit. Care Med. 153(6 Pt. 2), S2-S4.PubMedGoogle Scholar
  12. 12.
    Goldie, R. G. (1990), Receptors in asthmatic airways. Am. Rev. Respir. Dis. 141(3 Pt. 2), S151-S156.PubMedGoogle Scholar
  13. 13.
    Haddad, E. B., et al. (1996), Muscarinic and betaadrenergic receptor expression in peripheral lung from normal and asthmatic patients. Am. J. Physiol. 270(6 Pt. 1), L947-L953.PubMedGoogle Scholar
  14. 14.
    Ebina, M., et al. (1993). Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma. A 3-D morphometric study. Am. Rev. Respir. Dis. 148(3), 720–726.PubMedGoogle Scholar
  15. 15.
    Skloot, G., Permutt, S., and Togias, A. (1995), Airway hyperresponsiveness in asthma, a problem of limited smooth muscle relaxation with inspiration. J. Clin. Investig. 96(5), 2393–2403.PubMedCrossRefGoogle Scholar
  16. 16.
    Brown, R. H., et al. (2001), High-resolution computed tomographic evaluation of airway distensibility and the effects of lung inflation on airway caliber in healthy subjects and individuals with asthma. Am. J. Respir. Crit. Care Med. 163(4), 994–1001.PubMedGoogle Scholar
  17. 17.
    Seow, C. Y. and Stephens, N. L. (1988), Velocitylength-time relations in canine tracheal smooth musle. J. Appl. Physiol. 64(5), 2053–2057.PubMedGoogle Scholar
  18. 18.
    Solway, J. (2000), What makes the airways contract abnormally? Is it inflammation? Am. J. Respir. Crit. Care Med. 161(3 Pt. 2), S164-S167.PubMedGoogle Scholar
  19. 19.
    Jiang, H., et al. (1992). Ragweed sensitization-induced increase of myosin light chain kinase content in canine airway smooth muscle. Am. J. Respir. Cell Mol. Biol. 7(6), 567–573.PubMedGoogle Scholar
  20. 20.
    Jiang, H., et al. (1992), Bronchial smooth muscle mechanics of a canine model of allergic airway hyperresponsiveness. J. Appl. Physiol. 72(1), 39–45.PubMedGoogle Scholar
  21. 21.
    Mitchell, R. W., et al. (1993). Effect of airway inflammation on smooth muscle shortening and contractility in guinea pig trachealis. Am. J. Physiol. 265(6 Pt. 1), L549-L554.PubMedGoogle Scholar
  22. 22.
    Fan, T., et al. (1997). Airway responsiveness in two inbred strains of mouse isparate in IgE and IL-4 production. Am. J. Respir. Cell Mol. Biol. 17(2), 156–163.PubMedGoogle Scholar
  23. 23.
    Mitchell, R. W., et al. (1994), Passive sensitization of human bronchi augments smooth muscle shortening velocity and capacity. Am. J. Physiol. 267(2 Pt. 1), L218-L222.PubMedGoogle Scholar
  24. 24.
    Stephens, N. L., et al. (1999), Airway hyperreactivity, direct smooth muscle approach. Pulm. Pharmacol. Ther. 12(2), 97–101.PubMedCrossRefGoogle Scholar
  25. 25.
    Shen, X., et al. (1997), Mechanisms for the mechanical response of airway smooth muscle to length oscillation. J. Appl. Physiol. 83(3), 731–738.PubMedGoogle Scholar
  26. 26.
    Gerthoffer, W. T. and Gunst, S. J. (2001), Invited review: focal adhesion and small heat shock proteins in the regulation of actin remodeling and contractility in smooth muscle. J. Appl. Physiol. 91(2), 963–972.PubMedGoogle Scholar
  27. 27.
    Tang, D. D. and Gunst, S. J. (2001), Depletion of focal adhesion kinase by antisense deperesses contractile activation of smooth muscle. Am. J. Physiol. Cell Physiol. 280(4), C874-C883.PubMedGoogle Scholar
  28. 28.
    Fredberg, J. J., et al. (1999), Perturbed equilibrium of myosin binding in airway smooth muscle and its implications in bronchospasm. Am. J. Respir. Crit. Care Med. 159(3), 959–967.PubMedGoogle Scholar
  29. 29.
    Fredberg, J. J., et al. (1997), Airway smooth muscle, tidal stretches, and dynamically determined contractile states. Am. J. Respir. Crit. Care Med. 156(6), 1752–1759.PubMedGoogle Scholar
  30. 30.
    Seow, C. Y., Pratusevich, V. R., and Ford, L. E. (2000). Series-to-parallel transition in the filament lattice of airway smooth muscle. J. Appl. Physiol. 89(3), 869–876.PubMedGoogle Scholar
  31. 31.
    Ford, L. E., Seow, C. Y., and Pratusevich, V. R. (1994). Plasticity in smooth muscle, a hypothesis. Can. J. Physiol. Pharmacol. 72(11), 1320–1324.PubMedGoogle Scholar
  32. 32.
    Kuo, K. H., et al. (2001), Myosin thick filament lability induced by mechanical strain in airway smooth muscle. J. Appl. Physiol. 90(5), 1811–1816.PubMedGoogle Scholar
  33. 33.
    Lakser, O. J., Lindeman, R., and Fredberg, J. J. (2002), Inhibition of the p38 MAP kinase pathway destabilizes smooth muscle length during physiological loading. Am. J. Physiol. Lung Cell Mol. Physiol. 282(5), L1117-L1121.PubMedGoogle Scholar
  34. 34.
    Yamboliev, I. A., et al. (2000), Evidence for modulation of smooth muscle force by the p38 MAP kinase/HSP27 pathway. Am. J. Physiol. Heart Circ. Physiol. 278(6), H1899-H1907.PubMedGoogle Scholar
  35. 35.
    Hedges, J. C., et al. (1999). A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration. J. Biol. Chem. 274(34), 24,211–24,219.CrossRefGoogle Scholar
  36. 36.
    Larsen, J. K., et al. (1997). Phosphorylation of the 27-kDa heat shock protein via p38 MAP kinase and MAPKAP kinase in smooth muscle. Am. J. Physiol. 273(5 Pt. 1), L930-L940.PubMedGoogle Scholar
  37. 37.
    Pollard, T. D. and Cooper, J. A. (1986), Actin and actin-binding proteins. A critical evaluation of mechanisms and functions. Annu. Rev. Biochem. 55, 987–1035.PubMedCrossRefGoogle Scholar
  38. 38.
    Bamburg, J. R. (1999), Proteins of the ADF/cofilin family, essential regulators of actin dynamics. Annu. Rev. Cell Dev. Biol. 15(1), 185–230.PubMedCrossRefGoogle Scholar
  39. 39.
    Hautmann, M. B., et al. (1997), Angiotensin II-induced stimulation of smooth muscle {alpha}-actin expression by serum response factor and the homeodomain transcription factor MHox. Circ. Res. 81(4), 600–610.PubMedGoogle Scholar
  40. 40.
    Sotiropoulos, A., et al. (1999). Signal-regulated activation of serum response factor is mediated by changes in actin dynamics. Cell 98(2), 159–169.PubMedCrossRefGoogle Scholar
  41. 41.
    Mack, C. P., et al. (2001), Smooth muscle differentiation marker gene expression is regulated by rhoA-mediated actin polymerization. J. Biol. Chem.. 276(1), 341–347.PubMedCrossRefGoogle Scholar
  42. 42.
    Yang, N., et al. (1998), Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature 393(6687), 809–812.PubMedCrossRefGoogle Scholar
  43. 43.
    Maekawa, M., et al. (1999). Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285(5429), 895–898.PubMedCrossRefGoogle Scholar
  44. 44.
    Croxton, T. L., Lande, B., and Hirshman, C. A. (1998), Role of G proteins in agonist-induced Ca2+ sensitization of tracheal smooth muscle. Am. J. Physiol. Lung Cell Mol. Physiol. 275(4), L748-L755.Google Scholar
  45. 45.
    Niwa, R., et al. (2002). Control of actin reorganization by Slingshot, a family of phosphatases that dephosphorylate ADF/cofilin. Cell 108(2), 233–246.PubMedCrossRefGoogle Scholar
  46. 46.
    Buss, F. and Jockusch, B. M. (1989). Tissue-specific expression of profilin. FEBS Lett. 249(1) 31–34.PubMedCrossRefGoogle Scholar
  47. 47.
    Holt, M. R. and Koffer, A. (2001). Cell motility, proline-rich proteins promote protrusions. Trends Cell Biol. 11(1), 38–46.PubMedCrossRefGoogle Scholar
  48. 48.
    Bear, J. E., Krause, M., and Gertler, F. B. (2001), Regulating cellular actin assembly. Curr. Opin. Cell. Biol. 13(2), 158–166.PubMedCrossRefGoogle Scholar
  49. 49.
    Hamada, K., et al. (2000), Structural basis of the membrane-targeting and unmasking mechanisms of the radixin FEMR domain. EMBO J. 19(17), 4449–4462.PubMedCrossRefGoogle Scholar
  50. 50.
    Harbeck, B., et al. (2000). Phosphorylation of the vasodilator-stimulated phosphoprotein regulates its interaction with actin. J. Biol. Chem. 275(40), 30,817–30,825.CrossRefGoogle Scholar
  51. 51.
    Wear, M. A., Schafer, D. A., and Cooper, J. A. (2000). Actin dynamics, assembly and disassembly of actin networks. Curr. Biol. 10(24), R891-R895.PubMedCrossRefGoogle Scholar
  52. 52.
    Nakano, K., et al. (1999), Distinct actions and cooperative roles of ROCA and m Dia in rho small G protein-induced reorganization of the actin cytoskeleton in Madin-Darby canine kidney cells. Mol. Biol. Cell 10(8), 2481–2491.PubMedGoogle Scholar
  53. 53.
    Vaiskunaite, R., et al. (2000), Conformational activation of radixin by G13 protein alpha subunit. J. Biol. Chem. 275(34), 26,206–26,212.CrossRefGoogle Scholar
  54. 54.
    Sun, H. Q., et al. (1999), Gelsolin, a multifunctional actin regulatory protein. J. Biol. Chem. 274(47), 33,179–33,182.Google Scholar
  55. 55.
    Hart, M. C., Korshunova, Y. O., and Cooper, J. A. (1997). Vertebrates have conserved capping protein alpha isoforms with specific expression patterns. Cell Motil. Cytoskelet. 38(2), 120–132.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  • Nickolai O. Dulin
    • 1
  • Darren J. Fernandes
    • 1
  • Maria Dowell
    • 1
  • Shashi Bellam
    • 1
  • John McConville
    • 1
  • Oren Lakser
    • 2
  • Richard Mitchell
    • 1
  • Blanca Camoretti-Mercado
    • 1
  • Paul Kogut
    • 1
  • Julian Solway
    • 1
    Email author
  1. 1.Section of Pulmonary and Critical Care Medicine, Department of MedicineUniversity of ChicagoChicago
  2. 2.Department of PediatricsChildren's Memorial Hospital and Northwestern UniversityChicago

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