Published ahead of print on May 31, 2007, doi:10.1164/rccm.200609-1345OC Am. J. Respir. Crit. Care Med., Volume 176, Number 4, August 2007, 333-342 A more recent version of this article appeared on August 15, 2007
Submitted on September 19, 2006 Plasminogen is an Important Regulator in the Pathogenesis of a Murine Model of AsthmaCarmen M Swaisgood1,1 Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, OH, USA; Department of Pulmonary, Allergy and Critical Care Medicine and Department of Pathobiology, Lerner Research Institue of Cleveland Clinic, Cleveland, OH, USA, 2 Department of Pulmonary, Allergy and Critical Care Medicine and Department of Pathobiology, Lerner Research Institue of Cleveland Clinic, Cleveland, OH, USA, 3 Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, OH, USA * To whom correspondence should be addressed. E-mail: plowe{at}ccf.org.
Rationale: Asthma is a syndrome whose common pathogenic expression is inflammation of the airways. Plasminogen (Plg) 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: The host responses measured included lung morphometry, and inflammatory mediators and cell counts were assessed in brochoalveolar lavage fluid.
Main Results: Bronchoalveolar lavage demonstrated a marked increase in eosinophils and lymphocytes in ovalbumin-treated Plg+/+ mice; which were reduced to PBS-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, TNF- Key words: lung, knock-out mice, pulmonary inflammation, fibrinolysis
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and gelatinases, known mediators of asthma, were detected in bronchoalveolar lavage fluid of
ovalbumin-treated Plg+/+ mice, yet 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.
Conclusion: 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 suggest that plasminogen may be a therapeutic target for the treatment of asthma.
