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Understanding the pathophysiology of severe asthma to generate new therapeutic opportunities

Record type: Article

Although asthma is defined in terms of reversibility of airflow obstruction, as the disease becomes more severe and chronic, it adopts different characteristics, including a degree of fixed airflow obstruction and corticosteroid refractoriness. Underlying these phenotypes is evidence of airway wall remodeling, which should be distinguished from the increase in smooth muscle linked to airways hyperresponsiveness. Aberrant epithelial-mesenchymal communication leads to a chronic wound scenario, which is characterized by activation of the epithelial-mesenchymal trophic unit, epithelial damage, the laying down of new matrix, and greater involvement of neutrophils in the inflammatory response. In allergic asthmatic patients who remain symptomatic despite high-dose corticosteroid therapy, blockade of IgE with omalizumab confers appreciable clinical benefit. Chronic severe asthma is also accompanied by a marked increase in TNF-? production that might contribute to corticosteroid refractoriness. Based on this, TNF blockade with the soluble fusion protein entanercept produces improvement in asthma symptoms, lung function, and quality of life paralleled by a marked reduction in airways hyperresponsiveness. Identification of novel susceptibility genes, such as a disintegrin and metalloprotease 33 (ADAM33), will provide further targets against which to direct novel therapies for asthma, especially at the more severe end of the disease spectrum.
Abbreviations: ADAM, A disintegrin and metalloprotease; APP, Amyloid precursor peptide; BAL, Bronchoalveolar lavage; BHR, Bronchial hyperresponsiveness; COPD, Chronic obstructive pulmonary disease; ECM, Extracellular matrix; EMTU, Epithelial-mesenchymal trophic unit; LABA, Long-acting ?2-agonist; LTRA, Leukotriene receptor antagonist; SNP, Single nucleotide polymorphism; TIMP, Tissue inhibitor of metalloprotease

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Citation

Holgate, Stephen T., Holloway, John, Wilson, Susan, Howarth, Peter H., Haitchi, Hans Michael, Babu, Suresh and Davies, Donna E. (2006) Understanding the pathophysiology of severe asthma to generate new therapeutic opportunities Journal of Allergy and Clinical Immunology, 117, (3), pp. 496-506. (doi:10.1016/j.jaci.2006.01.039).

More information

Published date: March 2006
Keywords: severe asthma, airway remodeling, tumor necrosis factor, etanercept, anti-IgE, omalizumab, a disintegrin and metalloprotease 33, airway responsiveness, new treatments

Identifiers

Local EPrints ID: 27134
URI: http://eprints.soton.ac.uk/id/eprint/27134
ISSN: 0091-6749
PURE UUID: 41adc190-0329-41b1-a93e-016333848177
ORCID for John Holloway: ORCID iD orcid.org/0000-0001-9998-0464
ORCID for Hans Michael Haitchi: ORCID iD orcid.org/0000-0001-8603-302X

Catalogue record

Date deposited: 25 Apr 2006
Last modified: 17 Jul 2017 16:05

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