Bronchial hyperreactivity: pathogenesis and treatment options
Martina Antosova, Anna Strapkova, Jana Plevkova
DOI: 10.4236/ojmip.2011.13007   PDF   HTML   XML   7,363 Downloads   18,070 Views   Citations


This review is written to summarize and critically analyze pathogenesis of bronchial hyperreactivity (BHR) as an underlying outcome for suitable treatment options. It describes and discusses the role of genetic predisposition, inflammatory mediators and other endogenous factors (growth factors, nuclear transcription factors), neural regulation and proinflammatory neurotransmitter in the pathogenesis of BHR. Based on these data it provides brief insight into the treatment options, which could be applied to minimize symptoms of respiratory diseases characterized by BHR and successfully diminish the pathogenesis pathways involved.

Share and Cite:

Antosova, M. , Strapkova, A. and Plevkova, J. (2011) Bronchial hyperreactivity: pathogenesis and treatment options. Open Journal of Molecular and Integrative Physiology, 1, 43-51. doi: 10.4236/ojmip.2011.13007.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Grootendorst, D.C. and Rabe, K.F. (2004) Mechanisms of bronchial hyperreactivity in asthma and chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society, 1, 77-87. doi:10.1513/pats.2306025
[2] Joos, G.F. (2003) Bronchial hyperresponsiveness: Too complex to be useful? Current Opinion in Pharmacology, 3, 233-238. doi:10.1016/S1471-4892(03)00046-8
[3] Riccioni, G., Della Vecchia, R., Castronuovo, M., Di Pietro, V., Spoltore, R., De Benedictis, M., Di Iorio, A., Di Gioacchino, M. and Guagnano, M.T. (2002) Bronchial hyperresponsiveness in adults with seasonal and perennial rhinitis: Is there a link for asthma and rhinitis? International Journal of Immunopathology Pharmacology, 15, 69-74.
[4] Ernst, P., Ghezzo, H. and Becklake, M.R. (2002) Risk factors for bronchial hyperresponsiveness in late childhood and early adolescence. European Respiratory Journal, 20, 635-639. doi:10.1183/09031936.02.00962002
[5] Amin, K., Ekberg-Jansson, A., Lofdahl, C.G. and Venge, P. (2003) Relationship between inflammatory cells and structural changes in the lungs of asymptomatic and never smokers: A biopsy study. Thorax, 58, 135-142. doi:10.1136/thorax.58.2.135
[6] Grbac, I., Martinac, S., ?oko?evi?, M., Ron?evi?, S., Petri?, V. and Stan?i?, V. (2003) The pathogenesis of bronchial hyperreactivity in patients with allergic rhinitis. Acta Clinica Croatica, 42, 69-74.
[7] Postma, D.S., Kooppelman, G.H. and Meyers, D.A. (2000) The genetics of atopy and airway hyperresponsiveness. American Journal of Respiratory and Critical Care Medicine, 162, S118-S123.
[8] Larche, M., Robinson, D.S. and Kay, A.B. (2003) The role of T lymphocytes in the pathogenesis of asthma. Journal of Allergy Clinical Immunology, 111, 450-463. doi:10.1067/mai.2003.169
[9] Schmidt, D. (2001) Human isolated airways: An in vitro model for the investigation of airway smooth muscle physiology and its pharmacological modulation. Thesis. Leiden, Leiden University.
[10] Laprise, C. and Boulet, L.P. (1997) Asymptomatic airway hyperresponsiveness: A three-year follow-up. American Journal of Respiratory Critical Care Medicine, 156, 403-409.
[11] Amrani, Y., Moore, P.E., Hoffman, R., Shore, S.A. and Panettieri, R.A. Jr. (2001) Interferon-gamma modulates cysteinyl leukotriene receptor-1 expression and function in human airway myocytes. American Journal of Respiratory Critical Care Medicine, 164, 2098-2101.
[12] Widdicombe, J.G. (1998) Autonomic regulation: iNA- NC/eNANC. American Journal of Respiratory Critical Care Medicine, 158, S171-S175.
[13] Bardin, P.G., Dorward, M.A., Lampe, F.C., Franke, B. and Holgate, S.T. (1998) Effect of selective phosphodiesterase 3 inhibition on the early and late asthmatic responses to inhaled allergen. British Journal of Clinical Pharmacology, 45, 387-391. doi:10.1046/j.1365-2125.1998.t01-1-00689.x
[14] Barnes, P.J. (2004) Mediators of chronic obstructive pul- monary disease. Pharmacological Reviews, 56, 515-548. doi:10.1124/pr.56.4.2
[15] Barnes, P.J. and Karin, M. (1997) Nuclear factor-_B: A pivotal transcription factor in chronic inflammatory diseases. New England Journal of Medicine, 336, 1066- 1071. doi:10.1056/NEJM199704103361506
[16] Yang, M., Hogan, S.P., Henry, P.J., Matthaei, K.I., McKenzie, A.N.J., Young, I.G., Rothenberg, M.E. and Foster, P.S. (2001) Interleukin-13 mediates airways hyperreactivity through the IL-4 receptor-alpha chain and STAT-6 independently of IL-5 and eotaxin. American Journal of Respiratory Cell and Molecular Biology, 25, 522-530.
[17] Bielory, L. and Gandhi, R. (1994) Asthma and vitamin C. Annals of Allergy, 73, 89-96.
[18] Billington, C.K., Joseph, S.K., Swan, C., Scott, M.G., Jobson, T.M. and Hall, I.P. (1999) Modulation of human airway smooth muscle proliferation by type 3 phosphodiesterase inhibition. American Journal of Physiology, 276, L412-419.
[19] Shi, H.Z., Xiao, C.Q., Zhong, D., Qin, S.M., Liu, Y., Liang, G.R., Xu, H., Chen, Y.Q., Long, X.M. and Xie, Z.F. (1998) Effect of inhaled interleukin-5 on airway hyperreactivity and eosinophilia in asthmatics. American Journal of Respiratory Critical Care Medicine, 157, 204-209.
[20] Soussi-Gounni, A., Kontolemos, M. and Hamid, Q. (2001) Role of IL-9 in the pathophysiology of allergic diseases. Journal of Allergy and Clinical Immunology, 107, 575-582. doi:10.1067/mai.2001.114238
[21] Mukhopadhyay, S., Hoidal, J.R. and Mukherjee, T.K. (2006) Role of TNFalpha in pulmonary pathophysiology. Respiratory Research, 11, 125. doi:10.1186/1465-9921-7-125
[22] Thomas, P.S. and Heywood, G. (2002) Effects of inhaled tumour necrosis factor alpha in subjects with mild asthma. Thorax, 57, 774-778. doi:10.1136/thorax.57.9.774
[23] MacNee, W. (2001) Oxidants/antioxidants and chronic obstructive pulmonary disease: Pathogenesis to therapy. Novartis Foundation Symposium, 234, 169-188. doi:10.1002/0470868678.ch11
[24] Spicuzza, L., Barnes, P.J., Di Maria, G.U. and Belvisi, M.G. (2001) Effect of 8-isoprostaglandin F2_ on acetylcholine release from paraxympathetic nerves in guinea pig airways. European Journal of Pharmacology, 416, 231-234. doi:10.1016/S0014-2999(01)00882-2
[25] Barnes, P.J. and Karin, M. (1997) Nuclear factor-_B: A pivotal transcription factor in chronic inflammatory diseases. New England Journal of Medicine, 336, 1066- 1071. doi:10.1056/NEJM199704103361506
[26] Smith, L.J., Shamsuddin, M., Sporn, P.H., Denenberg, M. and Anderson, J. (1997) Reduced superoxide dismutase in lung cells of patients with asthma. Free Radical Biology and Medicine, 22, 1301-1307. doi:10.1016/S0891-5849(96)00550-3
[27] Boulet, L.P. (2003) Physiopathology of airway hyperresponsiveness. Current Allergy and Asthma Reports, 3, 66-71. doi:10.1007/s11882-003-0030-9
[28] Fattouh, R., Al-Garawi, A., Fattouh, M., Arias, K., Walker, T.D., Goncharova, S., Coyle, A.J., Humbles, A.A. ans Jordana, M. (2011) Eosinophils are dispensable for allergic remodelling and immunity in a model of house dust mite-induced airway disease. American Journal of Respiratory Critical Care Medicine, 183, 179-188. doi:10.1164/rccm.200905-0736OC
[29] Westergren-Thorsson, G., Chakir, J., Lafrenière-Allard, M.J., Boulet, L.P. and Tremblay, G.M. (2002) Correlation between airway responsiveness and proteoglycan production by bronchial fibroblasts from normal and asthmatic subjects. International Journal of Biochemistry and Cell Biology, 34, 1256-1267. doi:10.1016/S1357-2725(02)00058-4
[30] Fritz, D.K., Kerr, C., Fattouh, R., Llop-Guevara, A., Khan, W.I., Jordana, M. and Richards, C.D. (2011) A mouse model of airway disease: Oncostatin M-induced pulmonary eosinophilia, goblet cell hyperplasia, and airway hyperresponsiveness are STAT6 dependent, and interstitial pulmonary fibrosis is STAT6 independent. Journal of Immunology, 186, 1107-1118. doi:10.4049/jimmunol.0903476
[31] Bergeron, C. and Boulet, L.P. (2006) Structural changes in airway diseases: Characteristics, mechanisms, consequences, and pharmacologic modulation. Chest, 129, 1068-1087. doi:10.1378/chest.129.4.1068
[32] Meurs, H., Maarsingh, H. and Zaagsma, J. (2003) Arginase and asthma: Novel insights into nitric oxide homeostasis and airway hyperresponsiveness. Treasury Inflation Protected Securities, 24, 450-455. doi:10.1016/S0165-6147(03)00227-X
[33] Noga, O., Hanf, G. and Kunkel, G. (2003) Immunological and clinical changes in allergic asthmatics following treatment with omalizumab. International Archives of Allergy and Immunology, 131, S46-52. doi:10.1159/000070434
[34] Hamelmann, E. and Wahn, U. (2008) Anti-IgE therapy. Clinical Allergy Immunology, 21, 415-427.
[35] Kumar, R.K., Herbert, C., Thomas, P.S., Wollin, L., Beume, R., Yang, M., Webb, D.C. and Foster, P.S. (2003) Inhibition of inflammation and remodelling by roflumilast and dexamethasone in murine chronic asthma. Journal of Pharmacology and Experimental Therapeutics, 307, 349-355. doi:10.1124/jpet.103.053819
[36] Finkelman, F.D., Hogan, S.P., Hershey, G.K., Rotheberg, M.E. and Wills-Karp, M. (2010) Importance of cytokines in murine allergic airway disease and human asthma. Journal of Immunology, 184, 1663-1674. doi:10.4049/jimmunol.0902185
[37] Kotaru, C., Skowronski, M., Coreno, A. and McFadden, E.R. Jr. (2001) Inhibition of nitric oxide synthesis attenuates thermally induced asthma. Journal of Applied Physiology, 91, S703-708.
[38] Tomkinson, A., Duez, C., Cieslewicz, G., Pratt, J.C., Joetham, A., Shanafelt, M.C., Gundel, R. and Gelfand, E.W. (2001) A murine IL-4 receptor antagonist that inhibits IL-4- and IL-13-induced responses prevents antigen-induced airway eosinophilia and airway hyperresponsiveness. Journal of Immunology, 166, 5792-5800.
[39] Lee, C.G., Homer, R.J., Cohn, L., Link, H., Jung, S., Craft, J.E., Graham, B.S., Johnson, T.R. and Elias, J.A. (2002) Transgenic Overexpression of Interleukin (IL)-10 in the lung causes mucus metaplasia, tissue inflammation, and airway remodeling via IL-13-dependent and independent pathways. Journal of Biological Chemistry, 277, 35466-35474. doi:10.1074/jbc.M206395200
[40] Cheng, G., Arima, M., Honda, K., Hirata, H., Eda, F., Yoshida, N., Fukushima, F., Ishii, Y. and Fukuda, T. (2002) Anti-interleukin-9 antibody treatment inhibits airway inflammation and hyperreactivity in mouse asthma model. American Journal of Respiratory and Critical Care Medicine, 166, 409-416. doi:10.1164/rccm.2105079
[41] Amano, T., Nishihira, J. and Miki, I. (2007) Blockade of macrophage migration inhibitory factor (MIF) prevents the antigen-induced response in a murine model of allergic airway inflammation. Inflammation Research, 56, 24-31. doi:10.1007/s00011-007-5184-9
[42] Erin, E.M., Leaker, B.R., Nicholson, G.C., Tan, A.J., Green, L.M., Neighbour, H., Zacharasiewicz, A.S., Turner, J., Barnathan, E.S., Kon, O.M., Barnes, P.J. and Hansel, T.T. (2006) The effects of a monoclonal antibody directed against tumor necrosis factor-alpha in asthma. American Journal of Respiratory and Critical Care Medicine, 174, 753-762. doi:10.1164/rccm.200601-072OC
[43] Rennard, S.I., Fogarty, C., Kelsen, S., Long, W., Ramsdell, J., Allison, J., Mahler, D., Saadeh, C., Siler, T., Snell, P., Korenblat, P., Smith, W., Kaye, M., Mandel, M., Andrews, C., Prabhu, R., Donohue, J.F., Watt, R., Lo, K.H., Schlenker-Herceg, R., Barnathan, E.S. and Murray, J. (2007) COPD Investigators. The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Journal of Respiratory and Critical Care Medicine, 175, 926-934. doi:10.1164/rccm.200607-995OC
[44] Conroy, C.A. and Cattell, R. (2001) Infliximab treatment for Crohn’s disease. Postgraduate Medical Journal, 77, 436-440. doi:10.1136/pmj.77.909.436
[45] Kumar, R.K., Herbert, C., Webb, D.C., Li, L. and Foster, P.S. (2004) Effects of anticytokine therapy in a mouse model of chronic asthma. American Journal of Respiratory and Critical Care Medicine, 170, 1043-1048. doi:10.1164/rccm.200405-681OC
[46] Chang, C.J., Yang, Y.H., Liang, Y.C., Chiu, C.J., Chu, K.H., Chou, H.N. and Chiang, B.L. (2011) A novel phycobiliprotein alleviates allergic airway inflammation by modulating immune responses. American Journal of Respiratory and Critical Care Medicine, 183, 15-25. doi:10.1164/rccm.201001-0009OC
[47] Mokry, J. (2010) Inhibítory fosfodiesteráz pri ochoreniach dychacích ciest. Pediatria Pre Prax, 5, 101-107.
[48] Underwood, D.C., Bochnowicz, S., Osborn, R.R., Kotzer, C.J., Luttmann, M.A., Hay, D.W., Gorycki, P.D., Christensen, S.B. and Torphy, T.J. (1998) Antiasthmatic activity of the second-generation phosphodiesterase 4 (PDE4) inhibitor SB 207499 (Ariflo) in the guinea pig. Journal of Pharmacology and Experimental Therapeutics, 287, 988-995.
[49] Billington, C.K., Joseph, S.K., Swan, C., Scott, M.G., Jobson, T.M. and Hall, I.P. (1999) Modulation of human airway smooth muscle proliferation by type 3 phosphodiesterase inhibition. American Journal of Physiology, 276, L412-419.
[50] Myou, S., Fujimura, M., Kamio, Y., Ishiura, Y., Tachibana, H., Hirose, T., Hashimoto, T. and Matsuda, T. (1999) Bronchodilator effect of inhaled olprinone, a phosphodiesterase 3 inhibitor, in asthmatic patients. American Journal of Respiratory Critical Care Medicine, 160, 817-820.
[51] Joos, G.F. (2001) The role of neuroeffector mechanisms in the pathogenesis of asthma. Current Allergy and Asthma Reports, 1, 134-143. doi:10.1007/s11882-001-0081-8
[52] Kuss, H., Hoefgen, N., Johanssen, S., Kronbach, T. and Rundfeldt, C. (2003) In vivo efficacy in airway disease models of N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)- 5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12- 281), a selective phosphodiesterase 4 inhibitor for inhaled administration. Journal of Pharmacology and Experimental Therapeutics, 307, 373-385. doi:10.1124/jpet.103.053942
[53] Karish, S.B. and Gagnon, J.M. (2006) The potential role of roflumilast: The new phosphodiesterase-4 inhibitor. The Annals of Pharmacotherapy, 40, 1096-1104. doi:10.1345/aph.1E651
[54] Fernandes, D.J., Mitchell, R.W., Lakser, O., Dowell, M., Stewart, A.G. and Solway, J. (2003) Do inflammatory mediators influence the contribution of airway smooth muscle contraction to airway hyperresponsiveness in asthma? Journal of Applied Physiology, 95, 844-853.
[55] Holgate, S.T. (1998) The inflammation-repair cycle in asthma: The pivotal role of the airway epithelium. Clinical and Experimental Allergy, 5, 97-103. doi:10.1046/j.1365-2222.1998.028s5097.x
[56] Lipworth, B.J. (2005) Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet, 365, 167-175. doi:10.1016/S0140-6736(05)17708-3
[57] Essayan, D.M. (2001) Cyclic nucleotide phosphodiesterases. Journal of Allergy and Clinical Immunology, 108, 671-680. doi:10.1067/mai.2001.119555
[58] Finotto, S., De Sanctis, G.T., Lehr, H.A., Herz, U., Buerke, M., Schipp, M., Bartsch, B., Atreya, R., Schmitt, E., Galle, P.R., Renz, H. and Neurath, M.F. (2001) Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression. Journal of Experimental Medicine, 193, 1247-1260. doi:10.1084/jem.193.11.1247
[59] Nadeem, A., Raj, H.G. and Chhabra, S.K. (2008) Effect of vitamin E supplementation with standard treatment on oxidant-antioxidant status in chronic obstructive pulmonary disease. Indian Journal of Medical Research, 128, S705-711.
[60] Cuzzocrea, S., Riley, D.P., Caputi, A.P. and Salvemini, D. (2001) Antioxidant therapy: A new pharmacological approach in shock, inflammation, and ischemia/reperf- usion injury. Pharmacological Reviews, 53, S135-159.
[61] Strapková, A., Nosá?ová, G., Adamicová, K. and Gia?ová, D. (1997) Antioxidants in the respiratory system. Bratisl Lek Listy, 98, 527-530.
[62] Bielory, L. and Gandhi, R. (1994) Asthma and vitamin C. Annals of Allergy, 73, S89-96.
[63] Strapková, A. and Nosá?ová, G. (2001) Nitric oxide and airway reactivity. Bratisl Lek Listy, 102, S345-350.
[64] Behr, J., Maier, K., Degenkolb, B., Krombach, F. and Vogelmeier, C. (1997) Antioxidative and clinical effects of high-dose N-acetylcysteine in fibrosing alveolitis. Adjunctive therapy to maintenance immunosuppression. American Journal of Respiratory and Critical Care Medicine, 156, S1897-1901.

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.