fondaparinux and Hyperplasia

Previous studies have demonstrated that dysregulated coagulation and fibrinolysis contribute to the pathogenesis of asthma.. The role of procoagulant factor X in a murine model of ovalbumin (OVA)-induced asthma was investigated.. Biochemical, cellular, and physiologic in vivo and in vitro approaches were used to determine effects of factor X on the asthmatic response in mice.. 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.. 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.

Topics: Amphiregulin; Animals; Asthma; Bronchoalveolar Lavage Fluid; Cells, Cultured; Collagen; Disease Models, Animal; EGF Family of Proteins; Factor Xa; Factor Xa Inhibitors; Fondaparinux; Glycoproteins; Goblet Cells; Humans; Hydroxyproline; Hyperplasia; Intercellular Signaling Peptides and Proteins; Lung; Male; Mice; Mice, Inbred Strains; Mucins; Ovalbumin; Polysaccharides; Receptor, PAR-1; Receptor, PAR-2; Respiration; RNA, Messenger; Thrombin