26 Jul Loss of ADAM33 suppresses features of asthma, suggesting targeting ADAM33 as a potential new asthma therapy
MedicalResearch.com Interview with:
Hans Michael Haitchi, MD, MMed (INT)
PhD, PD, FHEA, PGcert
Associate Professor in Respiratory Medicine
Clinical and Experimental Sciences
Faculty of Medicine, University of Southampton
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: It is estimated that 300 million people worldwide suffer from asthma with 1 in 10/11 (USA/UK) children and 1 in 12 (USA & UK) adults suffering from the disorder. In children asthma is the most common long-term medical condition.
ADAM33 is an asthma gene. Small changes in the gene have been associated with increased twitchiness of the airways (bronchial hyperresponsiveness), loss of lung function in children and decline in lung function in the general population.
ADAM33 makes an enzyme, which is attached to cells in the airway muscles. When the enzyme loses its anchor to the cell surface, it is prone to going rogue around the lung causing poorer lung function in people who have asthma.
Our research, published in The Journal of Clinical Investigation (JCI) Insight, analysed human tissue samples and mice. Our experiments suggest that the human rogue ADAM33 protein is increased and enzymatically active in asthma. Furthermore, ADAM33 protein initiates airway remodelling (more muscle and blood vessels around the airways) without causing any inflammation in early life. However, when we switch off ADAM33 or prevent it from going rouge, the features of asthma – airway remodelling (more muscle and blood vessels around the airways), twitchiness and inflammation – will be reversed or reduced.
These findings identify ADAM33 as a novel target for disease modifying therapy in asthma.
MedicalResearch.com: What should readers take away from your report?
Response: Our studies have challenged the common paradigm that airway remodelling in asthma is a consequence of inflammation. Instead, we have shown that rogue human ADAM33 initiates airway remodelling that promotes allergic inflammation and twitchiness of the airways in the presence of allergen.
More importantly, we believe that if you block ADAM33 from going rogue or you stop its activity if it does go rogue, asthma could be prevented. ADAM33 initiated airway remodeling reduces the ability of the lungs to function normally, which is not prevented by current anti-inflammatory steroid therapy. Therefore, stopping this ADAM33 induced process would prevent a harmful effect that promotes the development of allergic asthma for many of the 25/5.4 million people in the USA/UK with the condition.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Current treatment for asthma consists of relieving the symptoms (reliever therapy) and treating the inflammation (anti-inflammatory therapy in form of steroids). However, none of these treatments does affect the airway remodeling part of asthma.
This study has provided the foundation and research tools for future research using our mouse models to test new drugs that block the enzyme of the rogue ADAM33 protein in the lungs. Blocking ADAM33 might prevent airway remodeling and development of allergic asthma in the presence of allergens at the origin of the disease. This could potential become a new “anti-remodeling” asthma therapy.
MedicalResearch.com: Is there anything else you would like to add?
Response: This finding radically alters our understanding of the field, to say the least. For years we have thought that airway remodeling is the result of the inflammation caused by an allergic reaction, but our research tells us otherwise.
Our research would have not be possible without the funding I received through a Medical Research Council (MRC) Clinician Scientist Fellowship that enabled me to spend valuable research training time at Cincinnati Children’s Hospital Medical Center, Ohio, USA as well as grants from the Asthma, Allergy and Inflammation (AAIR) charity and Faculty of Medicine in the UK.
Elizabeth R. Davies, Joanne F.C. Kelly, Peter H. Howarth, David I. Wilson, Stephen T. Holgate, Donna E. Davies, Jeffrey A. Whitsett, Hans Michael Haitchi. Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life. JCI Insight, 2016; 1 (11) DOI:10.1172/jci.insight.87632
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