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Coagulation factor Xa modulates airway remodeling in a murine model of asthma.

ABSTRACT: 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.

SUBMITTER: Shinagawa K

PROVIDER: S-EPMC1899277 | biostudies-literature | 2007 Jan

REPOSITORIES: biostudies-literature

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Coagulation factor Xa modulates airway remodeling in a murine model of asthma.

Shinagawa Kazuhiko K Martin J Andrew JA Ploplis Victoria A VA Castellino Francis J FJ

American journal of respiratory and critical care medicine 20061102 2

<h4>Rationale</h4>Previous studies have demonstrated that dysregulated coagulation and fibrinolysis contribute to the pathogenesis of asthma.<h4>Objective</h4>The role of procoagulant factor X in a murine model of ovalbumin (OVA)-induced asthma was investigated.<h4>Methods</h4>Biochemical, cellular, and physiologic in vivo and in vitro approaches were used to determine effects of factor X on the asthmatic response in mice.<h4>Measurements and main results</h4>Factor X transcript levels and facto ...[more]

PMID: 17082493

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Project description:Background:Purinergic receptors control cell proliferation, apoptosis, migration, inflammation, and cytokine secretion. Increased expression of specific purinergic receptors is reported in asthma. The role of purinergic P2Y6 receptors (P2Y6R) in asthma is controversial. Hypothesis:P2Y6R activation in asthma improves pulmonary function and reduces inflammation and smooth muscle amount. Methods:Female mice (C57/BL6, age 30 days) were randomly assigned to receive intranasal house dust mite (HDM) antigen (40 or 80 µg) or saline, 5 days/week, for 6 weeks. Randomly selected subgroups received intraperitoneal P2Y6R agonist prodrug (GC021109; 10 or 100 µg/kg weight/dose) simultaneously with HDM. After 6 weeks, lung function was measured. Lung lavage fluid (LLF) was used to measure total cell count, total protein, and cytokines. Immunohistochemistry for alpha smooth muscle actin (?-SMA) was done. Airway wall thickness was measured on micro-computed tomography (micro-CT) images. Results:Pulmonary function testing revealed a HDM dose-dependent airway hyperresponsiveness. Airway resistance was increased 2-fold while compliance was decreased by 50% at the higher HDM dose (P<0.05). GC021109 prevented these changes. HDM-exposed mice had elevated inflammatory cell and total protein levels in LLF which were prevented by GC021109 (P<0.05). HDM mice also had elevated LLF levels of interleukin (IL)-4, IL-5, IL-12, granulocyte colony stimulating factor, chemokine (C-X-C) motif ligand 1, and leukemia inhibitory factor that were reduced by GC021109 with a dose-dependent pattern. HDM mice had increased peribronchial and perivascular inflammatory cell infiltration and increased ?-SMA; these changes were absent with GC021109. Airway wall thickness measured on micro-CT images was increased after HDM exposure and significantly reduced by GC021109 treatment. Conclusion:The P2Y6R prodrug GC021109 inhibited allergen-induced changes in pulmonary function, inflammatory responses, and airway and vascular smooth muscle mass. P2Y6R activation may be an effective therapeutic maintenance strategy in asthma.

Dataset Information

Coagulation factor Xa modulates airway remodeling in a murine model of asthma.

Publications

Coagulation factor Xa modulates airway remodeling in a murine model of asthma.

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