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Prepublished online as a Blood First Edition Paper on April 17, 2003; DOI 10.1182/blood-2003-01-0227.
Submitted January 27, 2003
Accepted March 18, 2003
Plasminogen activator inhibitor type 1 deficiency does not Influence the outcome of murine pneumococcal pneumonia
Anita W Rijneveld*, Sandrine Florquin, Paul Bresser, Marcel Levi, Vivian de Waard, Roger Lijnen, Jaring S van der Zee, Peter Speelman, Peter Carmeliet, and Tom van der Poll
Department of Experimental Medicine, Academic Medical Center, Amsterdam, The Netherlands; Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
Department of Pulmonology, Academic Medical Center, Amsterdam, The Netherlands
Department of Biochemistry, Academic Medical Center, Amsterdam, The Netherlands
Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, Amsterdam, The Netherlands
Center for Molecular and vascular Biology, University of Leuven, Leuven, Belgium
Center for Transgene Technology and Gene Therapy, University of Leuven, Leuven, Belgium
* Corresponding author; email: a.w.rijneveld{at}amc.uva.nl.
Urokinase-type plasminogen activator (uPA) and its receptor uPAR are components of the fibrinolytic system, and important for an adequate immune response to respiratory tract infection in part through their role in the migration of inflammatory cells. PA inhibitor-1 (PAI-1) is the predominant inhibitor of soluble and receptor-bound uPA. To determine the role of PAI-1 in host defense against pneumococcal pneumonia, the following studies were performed: (1) patients with unilateral community acquired pneumonia demonstrated elevated PAI-1 concentrations together with decreased PA activity in BALF obtained from the infected , but not from the contralateral site; (2) mice with Streptococcus pneumoniae pneumonia displayed elevated PAI-1 protein and mRNA levels in their lungs; (3) PAI-1 gene deficient mice, however, had an unaltered immune response to pneumococcal pneumonia, as measured by cell recruitment into lungs, bacterial outgrowth and survival. Furthermore, plasminogen gene deficient mice also had an unremarkable defense against pneumococcal pneumonia. These data indicate that pneumonia is associated with inhibition of the fibrinolytic system at the site of the infection secondary to increased production of PAI-1; an intact fibrinolytic response is not required for an adequate host response to respiratory tract infection, however, suggesting that the previously described role of uPA and uPAR are restricted to their function in cell migration.
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