Beneficial and Detrimental Effects of Plasmin(ogen) during Infection and Sepsis in Mice

Plasmin has been proposed to be an important mediator during inflammation/infection. In this study, by using mice lacking genes for plasminogen, tissue-type plasminogen activator (tPA), and urokinase-type PA (uPA), we have investigated the functional roles of active plasmin in infection and sepsis. Two models were used: an infection model by intravenous injection of 1×10⁷ CFU of S. aureus, and a sepsis model by intravenous injection of 1.6×10⁸ CFU of S. aureus. We found that in the infection model, wild-type (WT) mice showed significantly higher survival rates than plasminogen-deficient (plg⁻/⁻) mice. However, in the sepsis model, plg⁻/⁻ or tPA⁻/⁻/uPA⁻/⁻ mice showed the highest survival rate whereas WT and tPA⁺/⁻/uPA⁺/⁻ mice showed the lowest survival rate, and plg⁺/⁻, tPA⁻/⁻, and uPA⁻/⁻ mice had an intermediate survival rate. These results indicate that the levels of active plasmin are critical in determining the survival rate in the sepsis, partly through high levels of inflammatory cytokines and enhanced STAT3 activation. We conclude that plasmin is beneficial in infection but promotes the production of inflammatory cytokines in sepsis that may cause tissue destruction, diminished neutrophil function, and an impaired capacity to kill bacteria which eventually causes death of these mice.