The airway epithelium dysfunction in the pathogenesis of asthma: The evidence


Asthma is traditionally defined as a chronic, multisystem, multicellular disease characterized by bronchial hyper-responsiveness (BHR) and lung inflammation. In this illness is particularly involving the airway epithelium as the place where the inflammation begins, develops and often returns through airway remodelling. In specific way there is also an evolving awareness of the active participation of structural elements, such as the airway epithelium, airway smooth muscle, and endothelium, in this process. The airway inflammation and remodelling together likely explain the clinical manifestations of asthma that is demonstrated by complicated respiratory manifestations in which wheeze occurring secondary to bronchoconstriction in the setting of airway hyper-responsiveness and mucous hypersecretion. This is confirmed by also the histopathological analyses of bronchial biopsies from asthmatic subjects. For this reason is very important to understand the physiological role of the airway epithelium and their changes during the exacerbation of disease.

Share and Cite:

Leonardi, S. , Coco, A. , Del Giudice, M. , Marseglia, G. and La Rosa, M. (2013) The airway epithelium dysfunction in the pathogenesis of asthma: The evidence. Health, 5, 331-338. doi: 10.4236/health.2013.52A044.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Tattersfield, A.E., Knox, A.J., Britton, J.R. and Hall, I.P. (2002) Asthma. Lancet, 360, 1313-1322. doi:10.1016/S0140-6736(02)11312-2
[2] Kabesch, M., Schedel, M., Carr, D., Woitsch, B., Fritzsch, C., Weiland, S.K. and von Mutius, E. (2006) IL-4/IL-13 pathway genetics strongly influence serum IgE levels and childhood asthma. Journal of Allergy and Clinical Immunology, 117, 269-274. doi:10.1016/j.jaci.2005.10.024
[3] Rigoli, L., Briuglia, S., Caimmi, S., Ferrau, V., Gallizzi, R., Leonardi, S., et al. (2011) Gene-environment interactions in childhood asthma. International Journal of Immunopathology and Pharmacology, 24, 41-47.
[4] Pascual, R.M. and Peters, S.P. (2005) Airway remodeling contributes to the progressive loss of lung function in asthma: An overview. Journal of Allergy and Clinical Immunology, 116, 477-486. doi:10.1016/j.jaci.2005.07.011
[5] Pepe, C., Foley, S., Shan-non, J., Lemiere, C., Olivenstein, R., Ernst, P., et al. (2005) Differences in airway remodeling between subjects with severe and moderate asthma. Journal of Allergy and Clinical Immunology, 116, 544- 549. doi:10.1016/j.jaci.2005.06.011
[6] Tang, M.L., Wilson, J.W., Stewart, A.G. and Royce, S.G. (2006) Airway remodelling in asthma: Current understanding and implications for future therapies. Pharmacology & Therapeutics, 112, 474-488. doi:10.1016/j.pharmthera.2006.05.001
[7] Miraglia del Giudice, M., Marseglia, G.L., Leonardi, S., Tosca, M.A., Marseglia, A., Perrone, L., et al. (2011) Fractional exhaled nitric oxide measurements in rhinitis and asthma in children. International Journal of Im- munopathology and Pharmacology, 24, 29-32.
[8] Takeda, N., Sumi, Y., Prefontaine, D., Al Abri, J., Al Heialy, N., Al-Ramli, W., et al. (2009) Epithelium-derived chemokines induce airway smooth muscle cell migration. Clinical & Experimental Allergy, 39, 1018-1026. doi:10.1111/j.1365-2222.2009.03238.x
[9] Holgate, S.T. (2008) The airway epithelium is central to the pathogenesis of asthma. Allergology International, 57, 1-10. doi:10.2332/allergolint.R-07-154
[10] De Boer, W.I., Sharma, H.S., Baelemans, S.M., Hoogsteden, H.C., Lambrecht, B.N. and Braunstahl, G.J. (2008) Altered expression of epithelial junctional proteins in atopic asthma: Possible role in inflammation. Canadian Journal of Physiology and Pharmacology, 86, 105-112. doi:10.1139/Y08-004
[11] Davies, D.E. (2000) The role of the epithelium in airway remodelling in asthma. Proceedings of the American Tho- racic Society, 96, 678-682.
[12] Dekkers, B.G., Maarsingh, H., Meurs, H. and Gosens, R. (2009) Airway structural components drive airway smooth muscle remodelling in asthma. Proceedings of the American Thoracic Society, 6, 683-692. doi:10.1513/pats.200907-056DP
[13] James, A.L. and Wenzel, S. (2007) Clinical relevance of airway remodelling in airway diseases. European Respiratory Journal, 30, 134-155. doi:10.1183/09031936.00146905
[14] Hackett, T.L., Shaheen, F., Johnson, A., Wadsworth, S., Pechkovsky, D.V., Jacoby, D.B., et al. (2008) Characterization of side population cells from human airway epithelium. Stem Cells, 26, 2576-2585. doi:10.1634/stemcells.2008-0171
[15] Boxall, C., Holgate, S.T. and Davies, D.E. (2006) The contribution of transforming growth factor-{beta}and epidermal growth factor signalling to airway remodelling in chronic asthma. European Respiratory Journal, 27, 208-229. doi:10.1183/09031936.06.00130004
[16] Koppelman, G.H., Meyers, D.A., Howard, T.D., Zheng, S.L., Hawkins, G.A., Am-pleford, E.J., et al. (2009) Identification of PCDH1 as a novel susceptibility gene for bronchial hyper-responsiveness. American Journal of Respiratory and Critical Care Medicine, 180, 929-935. doi:10.1164/rccm.200810-1621OC
[17] Barbato, A., Turato, G., Baraldo, S., Bazzan, E., Calabrese, F., Panizzolo, C., et al. (2006) Epithelial damage and angiogenesis in the airways of children with asthma. American Journal of Respiratory and Critical Care Medicine, 174, 975-981. doi:10.1164/rccm.200602-189OC
[18] Jeffery, P.K. (2001) Remodeling in asthma and chronic obstructive lung disease. American Journal of Respira- tory and Critical Care Medicine, 164, S28-S38.
[19] Berger, P., Girodet, P.O., Begueret, H., Ousova, O., Perng, D.W., Marthan, R., et al. (2003) Tryp-tase-stimulated human airway smooth muscle cells induce cytokine synthesis and mast cell chemotaxis. The FASEB Journal, 17, 2139-2141.
[20] Leonardi, S., Vitaliti, G., Marseglia, G.L., Caimmi, D., Lionetti, E., Miraglia del Giudice, M., et al. (2012) Func- tion of the airway epithelium in asthma. Journal of Biological Regulators & Homeostatic Agents, 26, 41-48.
[21] Ramos-Barbon, D., Fraga-Iriso, R., Brienza, N.S., Montero-Martinez, C., Verea-Hernando, H., Olivenstein, R., et al. (2010) T cells localize with proliferating smooth muscle alphaactin+ cell compartments in asthma. American Journal of Respiratory and Critical Care Medicine, 182, 317- 324. doi:10.1164/rccm.200905-0745OC
[22] Holgate, S.T. (2007) Epithelium dysfunction in asthma. Journal of Allergy and Clinical Immunology, 120, 1233- 1244. doi:10.1016/j.jaci.2007.10.025
[23] Cohen, L., Tarsi, J., Ram-kumar, T., Horiuchi, T.K., Coch- ran, R., et al., and the NHLBI Severe Asthma Research Program (SARP) (2007) Epithelial cell proliferation con- tributes to airway remodeling in severe asthma. American Journal of Respiratory and Critical Care Medicine, 176, 138-145.
[24] Xiao, C., Puddicombe, S.M., Field, S. and Davies, D.E. (2011) Detective epithelial barrier function in asthma. Journal of Allergy and Clinical Immunology, 128, 549- 556. doi:10.1016/j.jaci.2011.05.038
[25] Hammad, H. and Lambrecht, B.N. (2008) Dendritic cells and epithelial cells: Linking innate and adaptive immunity in asthma. Nature Reviews Immunology, 8, 193-204. doi:10.1038/nri2275
[26] Ziegler, S.F. and Liu, Y.J. (2007) Thymic stromal lym- phopoietin in normal and pathogenic T cell development and function. Nature Immunology, 7, 709-714. doi:10.1038/ni1360
[27] Allakhverdi, Z., Comeau, M.R., Jes-sup, H.K., Yoon, B.R., Brewer, A., Chartier, S., et al. (2007) Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and po- tently activates mast cells. The Journal of Experimental Medicine, 204, 253-258. doi:10.1084/jem.20062211
[28] Ying, S., O’Connor, B., Ratoff, J., Meng, Q., Mallett, K., Cousins, D., et al. (2005) Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. The Journal of Immunology, 174, 8183- 8190.
[29] Pégorier, S., Arouche, N., Dombret, M.C., Aubier, M. and Pretolani, M. (2007) Augmented epithelial endothelin-1 expression in refractory asthma. Journal of Allergy and Clinical Immunology, 120, 1301-1307. doi:10.1016/j.jaci.2007.09.023
[30] Zhao, Y., Usatyuk, P.V., Gorshkova, I.A., He, D., Wang, T., Moreno-Vinasco, L., et al. (2009) Regulation of COX- 2 expression and IL-6 release by particulate matter in airway epithelial cells. American Journal of Respiratory Cell and Molecular Biology, 40, 19-30. doi:10.1165/rcmb.2008-0105OC
[31] Gereke, M., Jung, S., Buer, J. and Bruder, D. (2009) Alveolar type II epithelial cells present antigen to CD4(1) T cells and induce Foxp3(1) regula-tory T cells. American Journal of Respiratory and Critical Care Medicine, 179, 344-355. doi:10.1164/rccm.200804-592OC
[32] Schmidt, M., Sun, G., Stacey, M.A., Mori, L. and Mattoli, S. (2003) Identification of circulating fibrocytes as pre- cursors of bronchial myofibroblasts in asthma. The Jour- nal of Immunology, 171, 380-389.
[33] Del Giudice, M.M., Pedullà, M., Brunese, F.P., Capristo, A.F., Capristo, C., Tosca, M.A., Leonardi, S. and Ciprandi, G. (2010) Neutrophilic cells in sputum of allergic asth-matic children. European Journal of inflammation, 8, 151-156.
[34] O’Byrne, P.M., Pedersen, S., Lamm, C.J., Tan, W.C., Busse, W.W.; START Investigators Group (2009) Severe exacerbations and decline in lung function in asthma. American Journal of Respiratory and Critical Care Medi- cine, 179, 19-24. doi:10.1164/rccm.200807-1126OC
[35] Turato, G., Barbato, A., Baraldo, S., Zanin, M.E., Bazzan, E., Lokar-Oliani, K., et al. (2008) Nonatopic children with multitrigger wheezing have airway pathology comparable to atopic asthma. American Journal of Respiratory and Critical Care Medicine, 178, 476-482. doi:10.1164/rccm.200712-1818OC
[36] Saunders, R., Siddiqui, S., Kaur, D., Doe, C., Sutcliffe, A., Hollins, F., et al. (2009) Fibrocyte localization to the airway smooth muscle is a feature of asthma. Journal of Allergy and Clinical Immunology, 123, 376-384. doi:10.1016/j.jaci.2008.10.048
[37] El-Shazly, A., Berger, P., Girodet, P.O., Ousova, O., Fayon, M., Vernejoux, J.M., et al. (2006) Fraktalkine produced by airway smooth muscle cells contributes to mast cell recruitment in asthma. The Journal of Immu- nology, 176, 1860-1868.
[38] Hollins, F., Kaur, D., Yang, W., Cruse, G., Saunders, R., Sutcliffe, A., et al. (2008) Human airway smooth muscle promotes human lung mast cell survival, proliferation, and constitutive activation: Cooperative roles for CADM1, stem cell factor, and IL-6. The Journal of Immunology, 181, 2772-2780.
[39] Koff, J.L., Shao, M.X., Ueki, I.F. and Nadel, J.A. (2008) Multiple TLRs activate EGFR via a signaling cascade to produce innate immune responses in airway epithelium. American Journal of Physiology-Lung Cel-lular and Molecular Physiology, 294, L1068-L1075. doi:10.1152/ajplung.00025.2008
[40] Kunzmann, S., Schmidt-Weber, C., Zingg, J.M., Azzi, A., Kramer, B.W., Blaser, K., et al. (2007) Connective tissue growth factor expression is regulated by histamine in lung fibroblasts: Potential role of histamine in airway remodelling. Journal of Allergy and Clinical Immunology, 119, 1398-1407. doi:10.1016/j.jaci.2007.02.018
[41] Léguillette, R., Laviolette, M., Bergeron, C., Zitouni, N., Kogut, P., Solway, J., et al. (2009) Myosin, transgelin, and myosin light chain kinase: Expression and function in asthma. American Journal of Respiratory and Critical Care Medicine, 179, 194-204. doi:10.1164/rccm.200609-1367OC
[42] Simcock, D.E., Ka-nabar, V., Clarke, G.W., Mahn, K., Karner, C., O’Connor, B.J., et al. (2008) Induction of angiogenesis by airway smooth muscle from patients with asthma. American Journal of Respiratory and Critical Care Medicine, 178, 460-468. doi:10.1164/rccm.200707-1046OC
[43] Chetta, A., Zanini, A., Foresi, A., D’Ippolito, R., Tipa, A., Castagnaro, A., et al. (2005) Vascular endothelial growth factor up-regulation and bronchial wall remodelling in asthma. Clinical & Experimental Allergy, 35, 1437-1442. doi:10.1111/j.1365-2222.2005.02360.x
[44] Lommatzsch, M., Lindner, Y., Edner, A., Bratke, K., Kuepper, M. and Virchow, J.C. (2009) Adverse effects of salmeterol in asthma: A neuronal perspective. Thorax, 64, 763-769. doi:10.1136/thx.2008.110916
[45] Araya, J., Cambier, S., Markovics, J.A., Wolters, P., Jablons, D., Hill, A., et al. (2007) Squamous metaplasia amplifies pathologic epitheli-al-mesenchymal interactions in COPD patients. Journal of Clinical Investigation, 117, 3551-3562. doi:10.1172/JCI32526
[46] Rock, J.R., Randell, S.H. and Ho-gan, B.L.M. (2010) Airway basal steam cells: A perspective in their roles in epithelial homeostasis and remodelling. Disease Models and Mechanisms, 3, 545-556. doi:10.1242/dmm.006031
[47] Macchiarini, P., Jungebluth, P., Go, T., Asnaghi, M.A., Rees, L.E., Cogan, T.A., et al. (2008) Clinical transplant- tation of a tissue-engineered airway. Lancet, 372, 2023-2030. doi:10.1016/S0140-6736(08)61598-6
[48] Bousquet, J., Schünemann, H.J., Samolinski, B., Demoly, P., Baena-Cagnani, C.E., et al. (2012) Allergic Rhinitis and its Impact on Asthma (ARIA): Achievements in 10 years and future needs. Journal of Allergy and Clinical Immunology, 130, 1049-1062.
[49] La Rosa, M., Lionetti, E., Leonardi, S., Salpietro, A., Bianchi, L., Salpietro, C., et al. (2011) Specific immunotherapy in children: The evidence. International Journal of Immunopathology and Pharmacology, 24, 69-78.
[50] Vitaliti, G., Leonardi, S., Miraglia del Giudice, M., Salpietro, A., Artusio, L., Caimmi, D., Arrigo, T., Salpietro, C., Ciprandi, G. and La Rosa, M. (2012) Mucosal immunity and sublingual immunotherapy in respiratory disorders. Journal of Biological Regulators & Homeostatic Agents, 26, 85-94.
[51] Bousquet, J., Scheinmann, P., Guinnepain, M.T., Perrin- Fayolle, M., Sauvaget, J., Tonnel, A.B., et al. (1999) Sub- lingual-swallow immunotherapy (SLIT) in patients with asthma due to housedust mites: A double-blind, placebo-controlled study. Allergy, 54, 249-260. doi:10.1034/j.1398-9995.1999.00916.x
[52] La Rosa, M., Ranno, C., André, C., Carat, F., Tosca, M.A. and Canonica, G.W. (1999) Double-blind placebo-controlled evaluation of sublingual swallow immunotherapy with standardized Parietaria judaica extract in children with allergic rhinoconjunctivitis. Journal of Allergy and Clinical Immunology, 104, 425-432. doi:10.1016/S0091-6749(99)70388-X
[53] Miraglia del Giudice, M., Marseglia, A., Leonardi, S., La Rosa, M., Salpietro, C., Arrigo, T., et al. (2011) Allergic rhinitis and quality of life in children. International Jour- nal of Immunopathology and Pharmacology, 24, 25-28.
[54] Bush, R.K., Swenson, C., Falherg, B., Evans, M.D., Esch, R. and Busse, W.W. (2011) House dust mite sublingual immunotherapy: Results of a US trial. Journal of Allergy and Clinical Immunology, 127, 974-981. doi:10.1016/j.jaci.2010.11.045
[55] Keles, S, Karakoc-Aydiner, E., Ozen, A., et al. (2011) A novel approach in allergeb specific immunotherapy: Combination of sublingual and subcutaneous routes. Journal of Allergy and Clinical Immunology, 128, 808-815. doi:10.1016/j.jaci.2011.04.033

Copyright © 2022 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.