title: Role of hyaluronan and hyaluronan-binding proteins in human asthma.
abstract: BACKGROUND
  The characteristics of human asthma are chronic inflammation and airway remodeling. Hyaluronan, a major extracellular matrix component, accumulates during inflammatory lung diseases, including asthma. Hyaluronan fragments stimulate macrophages to produce inflammatory cytokines. We hypothesized that hyaluronan and its receptors would play a role in human asthma.
  
  
  OBJECTIVE
  To investigate the role of hyaluronan and hyaluronan-binding proteins in human asthma.
  
  
  METHODS
  Twenty-one subjects with asthma and 25 healthy control subjects underwent bronchoscopy with endobronchial biopsy and bronchoalveolar lavage. Fibroblasts were cultured, and hyaluronan and hyaluronan synthase expression was determined at baseline and after exposure to several mediators relevant to asthma pathobiology. The expression of hyaluronan-binding proteins CD44, TLR (Toll-like receptor)-2, and TLR4 on bronchoalveolar lavage macrophages was determined by flow cytometry. IL-8 production by macrophages in response to hyaluronan fragment stimulation was compared.
  
  
  RESULTS
  Airway fibroblasts from patients with asthma produced significantly increased concentrations of lower-molecular-weight hyaluronan compared with those of normal fibroblasts. Hyaluronan synthase 2 mRNA was markedly increased in asthmatic fibroblasts. Asthmatic macrophages showed a decrease in cell surface CD44 expression and an increase in TLR2 and TLR4 expression. Macrophages from subjects with asthma showed an increase in responsiveness to low-molecular-weight hyaluronan stimulation, as demonstrated by increased IL-8 production.
  
  
  CONCLUSIONS
  Hyaluronan homeostasis is deranged in asthma, with increased production by fibroblasts and decreased CD44 expression on alveolar macrophages. Upregulation of TLR2 and TLR4 on macrophages with increased sensitivity to hyaluronan fragments suggests a novel proinflammatory mechanism by which persistence of hyaluronan fragments could contribute to chronic inflammation and airway remodeling in asthma.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Jiurong
authors.initials: J
authors.lastname: Liang
authors.forename: Dianhua
authors.initials: D
authors.lastname: Jiang
authors.forename: Yoosun
authors.initials: Y
authors.lastname: Jung
authors.forename: Ting
authors.initials: T
authors.lastname: Xie
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ingram
authors.forename: Tony
authors.initials: T
authors.lastname: Church
authors.forename: Simone
authors.initials: S
authors.lastname: Degan
authors.forename: Maura
authors.initials: M
authors.lastname: Leonard
authors.forename: Monica
authors.initials: M
authors.lastname: Kraft
authors.forename: Paul W
authors.initials: PW
authors.lastname: Noble
mesh_terms: D000328:Adult; D056151:Airway Remodeling; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology*; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C497483:CD44 protein, human; D016207:Cytokines; D018960:Hyaluronan Receptors; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases