Urokinase-type plasminogen activator (uPA) and its
receptor uPAR are components of the fibrinolytic system and are 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 bronchoalveolar lavage fluid (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.