title: Age dictates a steroid-resistant cascade of Wnt5a, transglutaminase 2, and leukotrienes in inflamed airways.
abstract: BACKGROUND
  Airway remodeling is a detrimental and refractory process showing age-dependent clinical manifestations that are mechanistically undefined. The leukotriene (LT) and wingless/integrase (Wnt) pathways have been implicated in remodeling, but age-specific expression profiles and common regulators remained elusive.
  
  
  OBJECTIVE
  We sought to study the activation of the LT and Wnt pathways during early- or late-onset allergic airway inflammation and to address regulatory mechanisms and clinical relevance in normal human bronchial epithelial cells (NHBEs) and nasal polyp tissues.
  
  
  METHODS
  Mice were sensitized with house dust mite (HDM) allergens from days 3, 15, or 60 after birth. Remodeling factors in murine bronchoalveolar lavage fluid, lung tissue, or human nasal polyp tissue were analyzed by means of Western blotting, immunoassays, or histology. Regulatory mechanisms were studied in cytokine/HDM-stimulated NHBEs and macrophages.
  
  
  RESULTS
  Bronchoalveolar lavage fluid LT levels were increased in neonatal and adult but reduced in juvenile HDM-sensitized mice. Lungs of neonatally sensitized mice showed increased 5-lipoxygenase levels, whereas adult mice expressed more group 10 secretory phospholipase A2, Wnt5a, and transglutaminase 2 (Tgm2). Older mice showed colocalization of Wnt5a and LT enzymes in the epithelium, a pattern also observed in human nasal polyps. IL-4 promoted epithelial Wnt5a secretion, which upregulated macrophage Tgm2 expression, and Tgm2 inhibition in turn reduced LT release. Tgm2, group 10 secretory phospholipase A2, and LT enzymes in NHBEs and nasal polyps were refractory to corticosteroids.
  
  
  CONCLUSIONS
  Our findings reveal age differences in LT and Wnt pathways during airway inflammation and identify a steroid-resistant cascade of Wnt5a, Tgm2, and LTs, which might represent a therapeutic target for airway inflammation and remodeling.
authors.affiliation: Center of Allergy and Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technical University of Munich and Helmholtz Center Munich, Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Dietz
authors.affiliation: Center of Allergy and Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technical University of Munich and Helmholtz Center Munich, Munich, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: de Los Reyes Jiménez
authors.affiliation: Faculty of Biology and Medicine, University of Lausanne, Service de Pneumologie, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Eva S
authors.initials: ES
authors.lastname: Gollwitzer
authors.affiliation: Center of Allergy and Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technical University of Munich and Helmholtz Center Munich, Munich, Germany; Department of Otolaryngology, Allergy Section, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Chaker
authors.affiliation: Center of Allergy and Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technical University of Munich and Helmholtz Center Munich, Munich, Germany.
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zissler
authors.affiliation: Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Olof P
authors.initials: OP
authors.lastname: Rådmark
authors.affiliation: Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL) and Ludwig-Maximilians-Universität, University Hospital Grosshadern, Munich, Germany.
authors.forename: Hoeke A
authors.initials: HA
authors.lastname: Baarsma
authors.affiliation: Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL) and Ludwig-Maximilians-Universität, University Hospital Grosshadern, Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
authors.affiliation: Center of Allergy and Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technical University of Munich and Helmholtz Center Munich, Munich, Germany.
authors.forename: Carsten B
authors.initials: CB
authors.lastname: Schmidt-Weber
authors.affiliation: Faculty of Biology and Medicine, University of Lausanne, Service de Pneumologie, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Marsland
authors.affiliation: Center of Allergy and Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technical University of Munich and Helmholtz Center Munich, Munich, Germany. Electronic address: Julia.esser@tum.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Esser-von Bieren
mesh_terms: D000375:Aging / Q000276:immunology*; D056151:Airway Remodeling / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology; D015153:Blotting, Western; D016535:Bronchial Hyperreactivity / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D019204:GTP-Binding Proteins / Q000276:immunology*; D006801:Humans; D015289:Leukotrienes / Q000276:immunology*; D051379:Mice; D009298:Nasal Polyps / Q000276:immunology; D011014:Pneumonia / Q000276:immunology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000276:immunology*; D000071818:Wnt-5a Protein / Q000276:immunology*
chemical_list: D015289:Leukotrienes; C000717608:TGM2 protein, human; D000071818:Wnt-5a Protein; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: Age; Wnt5a; airway inflammation; airway remodeling; allergy; asthma; bronchial epithelial cells; house dust mite; leukotrienes; lipid mediators; nasal polyps; secretory phospholipase A(2); transglutaminase 2