Mechanisms of Asthma and Implications for Its Prevention and Treatment: A Personal Journey

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|    Allergy Asthma Immunol Res. 2013 Jun;5:e174. English. Published online 2013 June 25.  Copyright © 2013 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease Mechanisms of Asthma and Implications for Its Prevention and Treatment: A Personal Journey Stephen T Holgate Faculty of Medicine University of Southampton, UK.  Correspondence to: Stephen T Holgate, MD, PhD, Clinical and Experimental Sciences, Mail Point, 810, Level F, South Block, Southampton General Hospital, Southampton, SO16 6YD, UK. Tel: +44-2380-796974; Fax: +44-2380-796992;Email: sth@soton.ac.uk  Received November 09, 2012; Accepted December 04, 2012. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract My research career has focused on the causes of asthma and its treatment. After establishing the key role that mast cells play in the inflammatory response in asthma, attention was turned towards understanding disease chronicity and variability across the lifecourse. Through a combination of studies on airway biopsies and primary cell cultures we have established that asthma is primarily an epithelial disease driven by increased environmental susceptibility to injury and an altered repair response as depicted by sustained activation of the epithelial mesenchymal trophic unit (EMTU) that is invoked in foetal branching morphogenesis. Varied activation of the EMTU connects the origins of asthma to its progression over time with involvement of epithelial susceptibility through impaired barrier and innate immune functions and altered mesenchymal susceptibility as exemplified by polymorphisms of the metalloprotease gene, ADAM33. Taken together these observations have led to a fundamental re-evaluation of asthma pathogenesis. Rather than placing allergic inflammation as the prime abnormality, it is proposed that the airway epithelium lies at the center of asthma pathogenesis, and that in conjunction with the underlying mesenchyme, it is the principle orchestrator of both the induction of asthma and its evolution over the lifecourse. This concept has provided 'the basis for a new preventative and therapeutic approach focused more on increasing the airways resistance to environmental insults rather than suppressing downstream inflammation once it is established. Keywords: Asthma, management, prevention, treatment.