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The role of ADAM33 in the pathogenesis of asthma

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Abstract

While asthma is a disorder of the conducting airways characterised by Th2-directed inflammation, a second set of mechanisms is being increasingly recognised as fundamental to disease chronicity and severity, for which the term “remodelling” has been used. The cellular and mediator responses underpinning airway remodelling involve aberrant communication between the airway epithelium and underlying mesenchyme, involving the generation of growth factors that lead to proliferation of fibroblasts and smooth muscle and the deposition of matrix proteins to cause airway wall thickening linked to bronchial hyperresponsiveness and fixed airflow obstruction. The identification of ADAM33 on chromosome 20p13 from positional cloning as a novel candidate gene involved in the pathogenesis of these structural and functional changes has opened the way to further insight into these processes that contribute to corticosteroid refractoriness. The preferential expression of ADAM33 in mesenchymal cells and its multiple molecular actions provide ample opportunity for incriminating this molecule in chronic asthma. Its association with progressive asthma and in predicting reduced lung function in young children suggest that ADAM33 has an important role in the natural history and possibly the origins of asthma, a disease unique to humans.

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Acknowledgements

The authors wish to thank the Medical Research Council, AAIR Charity and Wellcome Trust for supporting this work, Mrs. Chris Vincent and Kate Roberts for helping prepare the manuscript, and Dr. J.A. Holloway for her help in preparing the figure.

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Authors and Affiliations

  1. RCMB, Division of Infection, Inflammation and Repair, Southampton General Hospital, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK

    Julie A. Cakebread, H.-M. Haitchi, John W. Holloway, Robert M. Powell, Donna E. Davies & Stephen T. Holgate

  2. Division of Human Genetics, University of Southampton, Southampton, UK

    Julie A. Cakebread & John W. Holloway

  3. Genome Therapeutics Corporation, Woltham, Ma. 02453, USA

    Tim Keith

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  1. Julie A. Cakebread
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Correspondence to Stephen T. Holgate.

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Cakebread, J.A., Haitchi, HM., Holloway, J.W. et al. The role of ADAM33 in the pathogenesis of asthma. Springer Semin Immun 25, 361–375 (2004). https://doi.org/10.1007/s00281-003-0153-z

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