title: Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life.
abstract: Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene a disintegrin and metalloprotease 33 (ADAM33) acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble ADAM33 (sADAM33) is increased in asthmatic airways and plays a role in airway remodeling, independent of inflammation. Furthermore, remodeling and inflammation are both suppressed inAdam33-null mice after allergen challenge. When induced in utero or added ex vivo, sADAM33 causes structural remodeling of the airways, which enhances postnatal airway eosinophilia and bronchial hyperresponsiveness following subthreshold challenge with an aeroallergen. This substantial gene-environment interaction helps to explain the end-organ expression of allergic asthma in genetically susceptible individuals. Finally, we show that sADAM33-induced airway remodeling is reversible, highlighting the therapeutic potential of targeting ADAM33 in asthma.
authors.affiliation: The Brooke Laboratory, Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Davies
authors.affiliation: The Brooke Laboratory, Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Joanne F C
authors.initials: JF
authors.lastname: Kelly
authors.affiliation: National Institute for Health Research (NIHR) Southampton Respiratory Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.; Institute for Life Sciences, Stem Cells and Regeneration, Human Genetics, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Howarth
authors.affiliation: Institute for Life Sciences, Stem Cells and Regeneration, Human Genetics, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; Centre for Human Development, Stem Cells and Regeneration, Human Genetics, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: David I
authors.initials: DI
authors.lastname: Wilson
authors.affiliation: National Institute for Health Research (NIHR) Southampton Respiratory Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.; Institute for Life Sciences, Stem Cells and Regeneration, Human Genetics, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Holgate
authors.affiliation: The Brooke Laboratory, Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; National Institute for Health Research (NIHR) Southampton Respiratory Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.; Institute for Life Sciences, Stem Cells and Regeneration, Human Genetics, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Donna E
authors.initials: DE
authors.lastname: Davies
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.affiliation: The Brooke Laboratory, Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.; National Institute for Health Research (NIHR) Southampton Respiratory Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.; Institute for Life Sciences, Stem Cells and Regeneration, Human Genetics, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Hans Michael
authors.initials: HM
authors.lastname: Haitchi