In recent years, asthma has been defined primarily as an inflammatory disorder with emphasis on inflammation being the principle underlying pathophysiological characteristic driving airway obstruction and remodelling. Morphological abnormalities of asthmatic airway smooth muscle (ASM), the primary structure responsible for airway obstruction seen in asthma, have long been described, but surprisingly, until recently, relatively small number of studies investigated whether asthmatic ASM was also fundamentally different in its functional properties. Evidence from recent studies done on single ASM cells and on ASM-impregnated gel cultures have shown that asthmatic ASM is intrinsically hypercontractile. Several elements of the ASM contraction apparatus in asthmatics and in animal models of asthma have been found to be different from nonasthmatics. These differences include some regulatory contractile proteins and also some components of both the calcium-dependent and calcium-independent contraction signalling pathways. Furthermore, oxidative stress was also found to be heightened in asthmatic ASM and contributes to hypercontractility. Understanding the abnormalities and mechanisms driving asthmatic ASM hypercontractility provides a great potential for the development of new targeted drugs, other than the conventional current anti-inflammatory and bronchodilator therapies, to address the desperate unmet need especially in patients with severe and persistent asthma. 1. Introduction Asthma is a chronic inflammatory disease characterized by variable airflow obstruction and bronchial hyperreactivity associated with airway remodelling [1]. Most of asthma symptoms result from airflow obstruction caused by airway lumen narrowing. Although this narrowing is multifactorial in origin, abnormalities of airway smooth muscle (ASM) structure and function have been identified as one of the main causes [2]. Increased ASM mass has long been recognized as a major component of airway remodelling [3, 4]. More recently, asthmatic ASM was also found to be abnormal in its functional properties with increasing evidence showing intrinsic heightened contractility independent of other structural cells and independent of the asthma inflammatory milieu. In this paper we will examine the evidence of ASM hypercontractility in asthmatics, explore the potential mechanisms driving it, discuss its relevance, and briefly suggest its role in future asthma therapy. 2. Evidence of ASM Hypercontractility in Asthmatics Abnormalities of asthmatic ASM structure and morphology have been described by
References
[1]
E. D. Bateman, S. S. Hurd, P. J. Barnes et al., “Global strategy for asthma management and prevention: GINA executive summary,” European Respiratory Journal, vol. 31, no. 1, pp. 143–178, 2008.
[2]
J. G. Martin, A. Duguet, and D. H. Eidelman, “The contribution of airway smooth muscle to airway narrowing and airway hyperresponsiveness in disease,” European Respiratory Journal, vol. 16, no. 2, pp. 349–354, 2000.
[3]
H. Huber and K. Koesser, “pathology of bronchial asthma,” Archives of Internal Medicine, pp. 689–760, 1922.
[4]
A. James and N. Carroll, “Airway smooth muscle in health and disease; methods of measurement and relation to function,” European Respiratory Journal, vol. 15, no. 4, pp. 782–789, 2000.
[5]
R. A. Panettieri Jr., M. I. Kotlikoff, W. T. Gerthoffer et al., “Airway smooth muscle in bronchial tone, inflammation, and remodeling: basic knowledge to clinical relevance,” American Journal of Respiratory and Critical Care Medicine, vol. 177, no. 3, pp. 248–252, 2008.
[6]
A. M. Bramley, R. J. Thomson, C. R. Roberts, and R. R. Schellenberg, “Hypothesis: excessive bronchoconstriction in asthma is due to decreased airway elastance,” European Respiratory Journal, vol. 7, no. 2, pp. 337–341, 1994.
[7]
T. R. Bai, “Abnormalities in airway smooth muscle in fatal asthma: a comparison between trachea and bronchus,” American Review of Respiratory Disease, vol. 143, no. 2, pp. 441–443, 1991.
[8]
J. C. de Jongste, H. Mons, I. L. Bonta, and K. F. Kerrebijn, “In vitro responses of airways from an asthmatic patient,” European Journal of Respiratory Diseases, vol. 71, no. 1, pp. 23–29, 1987.
[9]
T. Bjorck, L. E. Gustafsson, and S. E. Dahlen, “Isolated bronchi from asthmatics are hyperresponsive to adenosine, which apparently acts indirectly by liberation of leukotrienes and histamine,” American Review of Respiratory Disease, vol. 145, no. 5, pp. 1087–1091, 1992.
[10]
R. G. Goldie, D. Spina, and P. J. Henry, “In vitro responsiveness of human asthmatic bronchus to carbachol, histamine, β-adrenoceptor agonists and theophylline,” British Journal of Clinical Pharmacology, vol. 22, no. 6, pp. 669–676, 1986.
[11]
J. A. Roberts, D. Raeburn, I. W. Rodger, and N. C. Thomson, “Comparison of in vivo airway responsiveness and in vitro smooth muscle sensitivity to methacholine in man,” Thorax, vol. 39, no. 11, pp. 837–843, 1984.
[12]
S. D. Whicker, C. L. Armour, and J. L. Black, “Responsiveness of bronchial smooth muscle from asthmatic patients to relaxant and contractile agonists,” Pulmonary Pharmacology, vol. 1, no. 1, pp. 25–31, 1988.
[13]
J. Cerrina, C. Labat, I. Haye-Legrande, B. Raffestin, J. Benveniste, and C. Brink, “Human isolated bronchial muscle preparations from asthmatic patients: effects of indomethacin and contractile agonists,” Prostaglandins, vol. 37, no. 4, pp. 457–469, 1989.
[14]
C. Y. Seow, R. R. Schellenberg, and P. D. Pare, “Structural and functional changes in the airway smooth muscle of asthmatic subjects,” American Journal of Respiratory and Critical Care Medicine, vol. 158, no. 5, pp. S179–S186, 1998.
[15]
X. Ma, Z. Cheng, H. Kong et al., “Changes in biophysical and biochemical properties of single bronchial smooth muscle cells from asthmatic subjects,” American Journal of Physiology, vol. 283, no. 6, pp. L1181–L1189, 2002.
[16]
H. Matsumoto, L. M. Moir, B. G. G. Oliver et al., “Comparison of gel contraction mediated by airway smooth muscle cells from patients with and without asthma,” Thorax, vol. 62, no. 10, pp. 848–854, 2007.
[17]
A. Sutcliffe, F. Hollins, E. Gomez, et al., “Increased nicotinamide adenine dinucleotide phosphate oxidase 4 expression mediates intrinsic airway smooth muscle hypercontractility in asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 185, pp. 267–274, 2012.
[18]
M. J. Berridge, “Inositol trisphosphate and calcium signalling mechanisms,” Biochimica et Biophysica Acta, vol. 1793, no. 6, pp. 933–940, 2009.
[19]
S. J. Gunst and D. D. Tang, “The contractile apparatus and mechanical properties of airway smooth muscle,” European Respiratory Journal, vol. 15, no. 3, pp. 600–616, 2000.
[20]
E. Roux and M. Marhl, “Role of sarcoplasmic reticulum and mitochondria in Ca2+ removal in airway myocytes,” Biophysical Journal, vol. 86, no. 4, pp. 2583–2595, 2004.
[21]
D. A. Deshpande, T. A. White, S. Dogan, T. F. Walseth, R. A. Panettieri, and M. S. Kannan, “CD38/cyclic ADP-ribose signaling: role in the regulation of calcium homeostasis in airway smooth muscle,” American Journal of Physiology, vol. 288, no. 5, pp. L773–L788, 2005.
[22]
A. J. Ammit, C. L. Armour, and J. L. Black, “Smooth-muscle myosin light-chain kinase content is increased in human sensitized airways,” American Journal of Respiratory and Critical Care Medicine, vol. 161, no. 1, pp. 257–263, 2000.
[23]
S. K. Kong, A. J. Halayko, and N. L. Stephens, “Increased myosin phosphorylation in sensitized canine tracheal smooth muscle,” American Journal of Physiology, vol. 259, no. 2, pp. L53–L56, 1990.
[24]
L. Benayoun, A. Druilhe, M. C. Dombret, M. Aubier, and M. Pretolani, “Airway structural alterations selectively associated with severe asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 167, no. 10, pp. 1360–1368, 2003.
[25]
P. G. Woodruff, G. M. Dolganov, R. E. Ferrando et al., “Hyperplasia of smooth muscle in mild to moderate asthma without changes in cell size or gene expression,” American Journal of Respiratory and Critical Care Medicine, vol. 169, no. 9, pp. 1001–1006, 2004.
[26]
C. E. Brightling, P. Bradding, F. A. Symon, S. T. Holgate, A. J. Wardlaw, and I. D. Pavord, “Mast-cell infiltration of airway smooth muscle in asthma,” The New England Journal of Medicine, vol. 346, no. 22, pp. 1699–1705, 2002.
[27]
H. Begueret, P. Berger, J. M. Vernejoux, L. Dubuisson, R. Marthan, and J. M. Tunon-de-Lara, “Inflammation of bronchial smooth muscle in allergic asthma,” Thorax, vol. 62, no. 1, pp. 8–15, 2007.
[28]
L. Woodman, S. Siddiqui, G. Cruse et al., “Mast cells promote airway smooth muscle cell differentiation via autocrine up-regulation of TGF-β1,” Journal of Immunology, vol. 181, no. 7, pp. 5001–5007, 2008.
[29]
F. Hollins, D. Kaur, W. Yang et al., “Human airway smooth muscle promotes human lung mast cell survival, proliferation, and constitutive activation: cooperative roles for CADM1, stem cell factor, and IL-6,” Journal of Immunology, vol. 181, no. 4, pp. 2772–2780, 2008.
[30]
D. Kaur, R. Saunders, F. Hollins et al., “Mast cell fibroblastoid differentiation mediated by airway smooth muscle in asthma,” Journal of Immunology, vol. 185, no. 10, pp. 6105–6114, 2010.
[31]
C. E. Brightling, F. A. Symon, S. T. Holgate, A. J. Wardlaw, I. D. Pavord, and P. Bradding, “Interleukin-4 and -13 expression is co-localized to mast cells within the airway smooth muscle in asthma,” Clinical and Experimental Allergy, vol. 33, no. 12, pp. 1711–1716, 2003.
[32]
J. C. Laporte, P. E. Moore, S. Baraldo et al., “Direct effects of interleukin-13 on signaling pathways for physiological responses in cultured human airway smooth muscle cells,” American Journal of Respiratory and Critical Care Medicine, vol. 164, no. 1, pp. 141–148, 2001.
[33]
S. K. Saha, M. A. Berry, D. Parker et al., “Increased sputum and bronchial biopsy IL-13 expression in severe asthma,” Journal of Allergy and Clinical Immunology, vol. 121, no. 3, pp. 685–691, 2008.
[34]
R. Léguillette, M. Laviolette, C. Bergeron et al., “Myosin, transgelin, and myosin light chain kinase expression and function in asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 179, no. 3, pp. 194–204, 2009.
[35]
K. Mahn, S. J. Hirst, S. Ying et al., “Diminished sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) expression contributes to airway remodelling in bronchial asthma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 26, pp. 10775–10780, 2009.
[36]
A. G. P. Guedes, J. Paulin, L. Rivero-Nava, H. Kita, F. E. Lund, and M. S. Kannan, “CD38-deficient mice have reduced airway hyperresponsiveness following IL-13 challenge,” American Journal of Physiology, vol. 291, no. 6, pp. L1286–L1293, 2006.
[37]
D. A. Deshpande, T. F. Walseth, R. A. Panettieri, and M. S. Kannan, “CD38/cyclic ADP-ribose-mediated Ca2+ signaling contributes to airway smooth muscle hyper-responsiveness,” The FASEB Journal, vol. 17, no. 3, pp. 452–454, 2003.
[38]
D. A. Deshpande, S. Dogan, T. F. Walseth et al., “Modulation of calcium signaling by interleukin-13 in human airway smooth muscle: role of CD38/cyclic adenosine diphosphate ribose pathway,” American Journal of Respiratory Cell and Molecular Biology, vol. 31, no. 1, pp. 36–42, 2004.
[39]
J. A. Jude, M. E. Wylam, T. F. Walseth, and M. S. Kannan, “Calcium signaling in airway smooth muscle,” Proceedings of the American Thoracic Society, vol. 5, no. 1, pp. 15–22, 2008.
[40]
T. Trian, G. Benard, H. Begueret et al., “Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma,” Journal of Experimental Medicine, vol. 204, no. 13, pp. 3173–3181, 2007.
[41]
Y. Chiba, K. Matsusue, and M. Misawa, “RhoA, a possible target for treatment of airway hyperresponsiveness in bronchial asthma,” Journal of Pharmacological Sciences, vol. 114, no. 3, pp. 239–247, 2010.
[42]
Y. Chiba, Y. Takada, S. Miyamoto, M. Mitsui-Saito, H. Karaki, and M. Misawa, “Augmented acetylcholine-induced, Rho-mediated Ca2+ sensitization of bronchial smooth muscle contraction in antigen-induced airway hyperresponsive rats,” British Journal of Pharmacology, vol. 127, no. 3, pp. 597–600, 1999.
[43]
Y. Chiba, H. Sakai, H. Wachi, H. Sugitani, Y. Seyama, and M. Misawa, “Upregulation of rhoA mRNA in bronchial smooth muscle of antigen-induced airway hyperresponsive rats,” Journal of Smooth Muscle Research, vol. 39, no. 6, pp. 221–228, 2003.
[44]
M. F. Moffatt, I. G. Gut, F. Demenais et al., “A large-scale, consortium-based genomewide association study of asthma,” The New England Journal of Medicine, vol. 363, no. 13, pp. 1211–1221, 2010.
[45]
M. F. Moffatt, M. Kabesch, L. Liang et al., “Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma,” Nature, vol. 448, no. 7152, pp. 470–473, 2007.
[46]
G. Cantero-Recasens, C. Fandos, F. Rubio-Moscardo, M. A. Valverde, and R. Vicente, “The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress,” Human Molecular Genetics, vol. 19, no. 1, pp. 111–121, 2009.
[47]
D. E. Doherty, “The pathophysiology of airway dysfunction,” American Journal of Medicine, vol. 117, supplement 12A, pp. 11S–23S, 2004.
[48]
P. Haldar, C. E. Brightling, B. Hargadon et al., “Mepolizumab and exacerbations of refractory eosinophilic asthma,” The New England Journal of Medicine, vol. 360, no. 10, pp. 973–984, 2009.
[49]
M. J. Leckie, A. Ten Brinke, J. Khan et al., “Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response,” The Lancet, vol. 356, pp. 2144–2148, 2000.
[50]
R. Djukanovi？, S. J. Wilson, M. Kraft et al., “Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 170, no. 6, pp. 583–893, 2004.
[51]
G. Cox, N. C. Thomson, A. S. Rubin et al., “Asthma control during the year after bronchial thermoplasty,” The New England Journal of Medicine, vol. 356, no. 13, pp. 1327–1337, 2007.
[52]
J. Bousquet, E. Mantzouranis, A. A. Cruz, et al., “Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma,” Journal of Allergy and Clinical Immunology, vol. 126, pp. 926–938, 2010.
