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Plasminogen Is an Important Regulator in the Pathogenesis of a Murine Model of Asthma

¹ Department of Molecular Cardiology, and ² Departments of Pulmonary, Allergy, and Critical Care Medicine, and Pathobiology, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio

Correspondence and requests for reprints should be addressed to Edward F. Plow, Ph.D., Cleveland Clinic, Department of Molecular Cardiology, NB50, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: plowe{at}ccf.org

Rationale: Asthma is a syndrome whose common pathogenic expression is inflammation of the airways. Plasminogen plays an important role in cell migration and is also implicated in tissue remodeling, but its role in asthma has not been defined.

Objectives: To test whether plasminogen is a critical component in the development of asthma.

Methods: We used a mouse model of ovalbumin-induced pulmonary inflammation in Plg^+/+, Plg^+/–, and Plg^–/– mice.

Measurements and Main Results: The host responses measured included lung morphometry, and inflammatory mediators and cell counts were assessed in bronchoalveolar lavage fluid. Bronchoalveolar lavage demonstrated a marked increase in eosinophils and lymphocytes in ovalbumin-treated Plg^+/+ mice, which were reduced to phosphate-buffered saline–treated control levels in Plg^+/– or Plg^–/– mice. Lung histology revealed peribronchial and perivascular leukocytosis, mucus production, and increased collagen deposition in ovalbumin-treated Plg^+/+ but not in Plg^+/– or Plg^–/– mice. IL-5, tumor necrosis factor-, and gelatinases, known mediators of asthma, were detected in bronchoalveolar lavage fluid of ovalbumin-treated Plg^+/+ mice, yet were reduced in Plg^–/– mice. Administration of the plasminogen inhibitor, tranexamic acid, reduced eosinophil and lymphocyte numbers, mucus production, and collagen deposition in the lungs of ovalbumin-treated Plg^+/+ mice.

Conclusions: The decreased inflammation in the lungs of Plg^–/– mice and its blockade with a plasminogen inhibitor indicate that plasminogen plays an important role in orchestrating the asthmatic response and suggests that plasminogen may be a therapeutic target for the treatment of asthma.

Key Words: lung • knockout mice • pulmonary inflammation • fibrinolysis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Asthma is a syndrome whose common pathogenic expression is inflammation of the airways. Plasminogen plays an important role in cell migration and is also implicated in tissue remodeling, but its role in asthma has not been defined. What This Study Adds to the Field The decreased inflammation in the lungs of Plg–/– mice and its blockade with a plasminogen inhibitor indicate that plasminogen plays an important role in asthma and suggest that plasminogen may be a therapeutic target for the treatment of the disease.

 

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