title: Coagulation factor Xa modulates airway remodeling in a murine model of asthma.
abstract: BACKGROUND
  Previous studies have demonstrated that dysregulated coagulation and fibrinolysis contribute to the pathogenesis of asthma.
  
  
  OBJECTIVE
  The role of procoagulant factor X in a murine model of ovalbumin (OVA)-induced asthma was investigated.
  
  
  METHODS
  Biochemical, cellular, and physiologic in vivo and in vitro approaches were used to determine effects of factor X on the asthmatic response in mice.
  
  
  RESULTS
  Factor X transcript levels and factor Xa activity were increased in lungs of asthmatic mice challenged with OVA, compared with controls treated with phosphate-buffered saline. Factor X was highly expressed in bronchoalveolar lavage fluid macrophages from asthmatic mice. Treatment of mice with the factor Xa inhibitor fondaparinux during the last 4 wk of OVA challenge resulted in the attenuation of airway hyperresponsiveness but did not alter infiltration of inflammatory cells into the lung. There was a significant decrease in the thickness of the mucosal layer and in lung collagen deposition in fondaparinux-treated mice. In vitro investigations using human mucus-producing NCI-H292 cells indicated that exogenous factor Xa enhanced mucin production in a dose-dependent manner. Levels of amphiregulin, a protein that induces mucin production, were also increased in cells stimulated by factor Xa.
  
  
  CONCLUSIONS
  The results of this study introduce a novel participant in the asthmatic response and indicate that factor Xa functions in airway remodeling in asthma by stimulating mucin production, through regulation of amphiregulin expression and collagen deposition.
authors.affiliation: WM Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Shinagawa
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Martin
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Ploplis
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Castellino
mesh_terms: D066258:Amphiregulin; D000818:Animals; D001249:Asthma / Q000201:enzymology* / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D066255:EGF Family of Proteins; D015951:Factor Xa / Q000235:genetics / Q000502:physiology*; D065427:Factor Xa Inhibitors; D000077425:Fondaparinux; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006909:Hydroxyproline / Q000032:analysis; D006965:Hyperplasia; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009077:Mucins / Q000378:metabolism; D010047:Ovalbumin / Q000494:pharmacology; D011134:Polysaccharides / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism; D012119:Respiration / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D065427:Factor Xa Inhibitors; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D009077:Mucins; D011134:Polysaccharides; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D010047:Ovalbumin; D003094:Collagen; D013917:Thrombin; D015951:Factor Xa; D000077425:Fondaparinux; D006909:Hydroxyproline