It is widely held that the plasminogen (Plg) system plays a role in inflammation through plasmin-mediated directional cell migration. However, substantial evidence for its involvement in the inflammatory response has been obtained from indirect studies and lacks firm biological confirmation. To directly characterize plasminogen's involvement in the inflammatory response, we used thioglycollate to induce a peritoneal inflammatory reaction in Plg(+/+),Plg(+/−), and Plg(−/−) mice. At 6 hours poststimulation, neutrophil recruitment into the peritoneum was maximal and similar between Plg(+/+), Plg(+/−), andPlg(−/−) mice. In contrast, monocyte recruitment was significantly diminished after 24 hours poststimulation inPlg(−/−) mice relative to Plg(+/+) mice. Lymphocyte recruitment also was blunted. Blood monocyte levels in these mice indicated that diminished recruitment into the peritoneum was not the result of a diminished source of cells in the circulation. Macrophage phagocytic function was similar between Plg(+/+) and Plg(−/−) mice. This study establishes a direct involvement of plasminogen in monocyte recruitment during a representative inflammatory response.

Acute and chronic pulmonary diseases are characterized by impaired fibrinolytic activity within the lung. To determine the role of the fibrinolytic system in regulating the pathologies associated with lung injury, we examined the effect of bleomycin, an agent that induces the development of pulmonary fibrosis, in mice deficient for plasminogen (Pg(-)(/-)), urokinase (u-PA(-)(/-)), urokinase receptor (u-PAR(-)(/-)), or tissue plasminogen activator (t-PA(-)(/-)), and in control wild-type (WT) mice. Pg(-)(/-) and t-PA(-)(/-) mice demonstrated an enhanced increase in lung collagen content relative to that observed in WT mice. Levels in u-PA(-)(/-) and u-PAR(-)(/-) mice were similar to those in WT mice. Histological analysis 14 days after lung injury confirmed enhanced interstitial fibrosis in Pg(-)(/-), u-PA(-)(/-), and t-PA(-)(/-) mice relative to WT and u-PAR(-)(/-) mice. Areas of pulmonary hemorrhage were observed in bleomycin-treated WT mice and not in Pg(-)(/-), u-PA(-)(/-), and u-PAR(-)(/-) mice or saline controls. Instead, extensive areas of fibrosis were present throughout the lungs of bleomycin-treated Pg(-)(/-) and u-PA(-)(/-) mice. A mixed phenotype (hemorrhage and fibrosis) was observed in t-PA(-)(/-) and Pg(+/-) mice. Hemosiderin-laden macrophages were abundant in the lungs of mice exhibiting hemorrhage and these mice were prone to an early death. Enhanced macrophage levels in the lungs and activation of matrix metalloelastase (MMP-12) were found in mice with a hemorrhage phenotype. The results of these studies indicate a role for the fibrinolytic system in acute lung injury and suggests that intra-alveolar hemorrhage is the result of basement membrane degradation through cell-mediated u-PA activation of Pg with possible involvement of matrix metalloproteinases. Absence of these two components of the fibrinolytic system, either urokinase or plasminogen, results in accelerated fibrosis.

Group A streptococci are capable of acquiring a surface-associated, unregulatable plasmin-like enzymatic activity when incubated in human plasma. The effect of this enzymatic activity on virulence of group A isolate CS101 was examined in a mouse skin infection model. Initial studies demonstrated enhanced virulence for bacteria preincubated in human plasma but not in plasminogen-depleted plasma. A direct correlation between surface-associated enzymatic activity and virulence was not observed; however, an association between virulence and the assembly of a surface-associated plasminogen activator that could activate mouse plasminogen was noted. This activity enhanced virulence in wild type but not in plg-/- plasminogen-deficient mice. These results support the hypothesis that acquisition of a surface-associated plasmin(ogen)-dependent enzymatic activity can contribute to the virulence of group A streptococcal invasive infections.