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The Expression and Function of the Asthma Susceptibility Gene, A University of Southampton Research Repository ePrints Soton Copyright © and Moral Rights for this thesis are retained by the author and/or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder/s. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given e.g. AUTHOR (year of submission) "Full thesis title", University of Southampton, name of the University School or Department, PhD Thesis, pagination http://eprints.soton.ac.uk UNIVERSITY OF SOUTHAMPTON FACULTY OF MEDCINE, HEALTH AND LIFE SCIENCES SCHOOL OF MEDICINE Division of Infection Inflammation & Repair (IIR) Allergy & Inflammation Research (AIR) The expression and function of the asthma susceptibility gene, A Disintegrin and Metalloprotease (ADAM) 33, in airways of normal and asthmatic subjects and in developing lungs By Hans Michael Haitchi MD, MMed Thesis for the degree of Doctor of Philosophy February 2008 Dedication To ἰχθύς (ichthys) & Gerhild i UNIVERSITY OF SOUTHAMPTON ABSTRACT FACULTY OF MEDCINE, HEALTH AND LIFE SCIENCES SCHOOL OF MEDICINE Doctor of Philosophy THE EXPRESSION AND FUNCTION OF THE ASTHMA SUSCEPTIBILITY GENE, A DISINTEGRIN AND METALLOPROTEASE (ADAM) 33, IN AIRWAYS OF NORMAL AND ASTHMATIC SUBJECTS AND IN DEVELOPING LUNGS by Hans Michael Haitchi Asthma affects 1 in 12 adults and 1 in 10 children in the UK. It is a complex disease involving genetic and environmental factors. ADAM33 is an asthma susceptibility gene whose polymorphic variation has been linked to asthma and bronchial hyperresponsiveness, as well as decline in lung function in asthma and COPD and reduced lung function in young children. ADAM33 mRNA is almost exclusively expressed in mesenchymal cells, such as fibroblasts, myofibroblasts and smooth muscle cells. These cells play an important role in modelling of the airways during lung development and in remodelling of the airway in established disease. As the function of ADAM33 and its role in asthma is not known, this thesis tested the hypotheses that: ADAM33 is differentially expressed in normal and asthmatic lungs; and ADAM33 is involved in embryonic/fetal lung development where the influence of an allergic maternal environment affects ADAM33 to contribute to the development of asthma. To test the hypothesis that ADAM33 is differentially expressed in asthma, bronchial biopsies and brushings from adult subjects were examined. Using RT-qPCR all previously described splice variants were detected in the biopsies. No disease specific difference for any of the mRNA splice variants could be detected. Using immunohistochemistry, it was shown, for the first time that ADAM33 is found mainly in the bronchial smooth muscle, consistent with its genetic association with BHR. Computer-aided image analysis of ADAM33 expression did not reveal a disease-specific difference, consistent with the mRNA data. No expression of ADAM33 could be demonstrated in bronchial brushings containing more than 95% epithelial cells. To test the hypothesis that ADAM33 is involved in embryonic lung development human embryonic lung (HEL) and mouse tissues were examined. Using RT-qPCR, the same splice variants were detected in HEL as in adult bronchial tissue, however Western blot analysis revealed an extra ADAM33 protein band in HELs compared to adult lungs suggesting a different role of ADAM33 in developing lung. Expression of ADAM33 increased in HELs from 7 to 9 weeks post conception and a similar increase occurred when HELs were cultured in a newly developed HEL explant culture system suggesting that this is a useful model for studying human lung development. ADAM33 could be successfully knocked down using siRNA in the mesenchymal progenitor cells grown in culture from HELs paving the way for knock-down in whole HEL tissue. When ADAM33 mRNA expression was studied during murine lung development it was detectable from as early as embryonic day 11 and two significant increments in expression could be seen. The first occurred during the pseudoglandular stage when spontaneous peristaltic contractions occur and the second one after birth when the lungs inflate at the beginning of air breathing, suggesting that mechanical forces might induce ADAM33. To test the hypothesis that ADAM33 and asthma are influenced by maternal allergy, a mouse model using bronchial hyperresponsiveness susceptible mice (A/J mice) was used. Maternal allergy was induced using ovalbumin and the offspring were studied for ADAM33 expression and lung function. Maternal allergy had a suppressive effect on ADAM33 mRNA directly after birth which was similar to the findings in HEL cultured for 18 days in the presence of IL-13. Maternal allergy also induced increased BHR to methacholine in 4 weeks old offspring. Although no direct causal relationship with ADAM33 was established, these findings suggest a potential gene-environment interaction. In conclusion this thesis provides novel data regarding the expression and localisation of ADAM33 in embryonic and adult lung. It also suggests a potential role for ADAM33 in lung development and highlights the effect that maternal allergy has on airway reactivity of offspring that carry the ADAM33 susceptibility gene, consistent with a role for ADAM33 in the early-life origins of asthma. ii Table of content Dedication .................................................................................................................... i ABSTRACT................................................................................................................ii Table of content.........................................................................................................iii List of figures.............................................................................................................. v List of tables.............................................................................................................viii List of tables.............................................................................................................viii List of movies...........................................................................................................viii Declaration of authorship......................................................................................... ix Acknowledgements..................................................................................................... x Definitions & abbreviations ..................................................................................... xi Chapter 1 Introduction .............................................................................. 1 1.1 What is asthma?............................................................................................................. 1 1.2 Asthma, a global and UK burden................................................................................... 1 1.3 Pathology & Pathophysiology ....................................................................................... 3 1.3.1 History .................................................................................................................... 3 1.3.2 Immunological features (Inflammation)................................................................. 4 1.3.3 Structural features................................................................................................... 9 1.3.4 Bronchial hyperresponsiveness............................................................................. 14 1.4 Treatment..................................................................................................................... 15 1.5 Genetics of Asthma...................................................................................................... 17 1.6 ADAM33 ..................................................................................................................... 20 1.6.1 Genetics of ADAM33........................................................................................... 20 1.6.2 Expression of ADAM33 ....................................................................................... 27 1.6.3 Function of ADAM33........................................................................................... 29 1.7 Early origin of asthma.................................................................................................. 36 1.8 Embryonic & Lung development................................................................................. 39 1.8.1 Human embryonic development........................................................................... 39 1.8.2 Embryonic lung development............................................................................... 43 1.8.3 Mechanisms of lung development ........................................................................ 46 1.8.4 The role of ADAMs in lung development ............................................................ 48 1.9 Summary and hypothesis ............................................................................................. 49 1.10 Aims..........................................................................................................................
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