Published ahead of print on February 11, 2005, doi:10.1164/rccm.200409-1251OC
Am. J. Respir. Crit. Care Med., Volume 171, Number 9, May 2005, 958-965
A more recent version of this article appeared on May 1, 2005
Submitted on September 24, 2004
Accepted on January 26, 2005
A Disintegrin and Metalloprotease 33 Expression in Asthmatic Airways and Human Embryonic Lungs
Hans Michael Haitchi1*, Robert M Powell1, Timothy J Shaw1, Peter H Howarth1, Susan J Wilson2, David I Wilson3, Stephen T Holgate1, and Donna E Davies1
1 Roger Brooke Laboratories, University of Southampton, Southampton General Hospital, Southampton, Hampshire, United Kingdom,
2 Histochemistry Research Unit, Allergy and Inflammation Research Division of Infection, Inflammation and Repair, University of Southampton, Southampton General Hospital, Southampton, Hampshire, United Kingdom,
3 Human Genetics Division, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, Hampshire, United Kingdom
* To whom correspondence should be addressed. E-mail: hmha{at}soton.ac.uk.
Abstract: Rationale: Polymorphic variation in A Disintegrin And Metalloprotease (ADAM)33 is strongly associated with asthma and bronchial hyperresponsiveness (BHR) in different populations. Objective and Methods: To study the role of ADAM33 in asthma, we investigated its expression in normal, asthmatic and embryonic airways using quantitative RT-PCR and immunochemistry. Results: Several ADAM33 mRNA splice variants were detected in bronchial biopsies and embryonic lung, however the beta isoform and variants encoding the metalloprotease domain were rare transcripts. Western blotting of bronchial biopsies confirmed the presence of multiple isoforms of ADAM33 which had molecular weights of 22, 37, 55 and 65kDa. Immunohistochemistry and laser confocal microscopy of adult bronchial biopsies showed that  -smooth muscle actin (SMA) and ADAM33 immunoreactivity were mostly co-localized to smooth muscle and isolated cells in the submucosa. There was no significant difference in ADAM33 mRNA amplicons or protein in asthmatic compared with control subjects. In developing lung, ADAM33 was found around bronchial tubes, however immunoreactivity was more widely distributed than SMA within undifferentiated mesenchyme; on Western blots an additional 25kDa ADAM33 variant was detected. Conclusions: Several ADAM33 protein isoforms occur in adult bronchial smooth muscle and in human embryonic bronchi and surrounding mesenchyme, strongly suggesting its importance in smooth muscle development and/or function which could explain its genetic association with BHR. The occurrence of ADAM33 in embryonic mesenchymal cells suggests that it may be involved in airway wall 'modelling' that contributes to the early life origins of asthma.
Key words: bronchial hyperresponsiveness, remodelling, mesenchymal cells, epithelial mesenchymal trophic unit (EMTU), lung development
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