Coagulation factor Xa modulates airway remodeling in a murine model of asthma.
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.
Shinagawa
Kazuhiko
K
WM Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN 46556, USA.
Martin
J Andrew
JA
Ploplis
Victoria A
VA
Castellino
Francis J
FJ
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
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