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Coagulation Factor Xa Modulates Airway Remodeling in a Murine Model of Asthma

W.M. Keck Center for Transgene Research and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana

Correspondence and requests for reprints should be addressed to Francis J. Castellino, Ph.D., 230 Raclin-Carmichael Hall, W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN 46556. E-mail: fcastell{at}nd.edu

Rationale: 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.

Measurements and Main 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.

Key Words: coagulation protein • airway hyperresponsiveness • mucus production • amphiregulin

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Previous results implied that an imbalance in coagulation and fibrinolysis contributes to the pathologic events associated with asthma, but their mechanistic roles in these processes have not been elucidated. What This Study Adds to the Field This study suggests that coagulation protein factor Xa may be involved in the regulation of asthma.

 

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