Polymorphonuclear leucocytes have two opposing roles in fibrinolysis

Area of Science:

• Biochemistry
• Hematology
• Immunology

Background:

• Polymorphonuclear leucocytes (PMN) play a crucial role in resolving human thrombi, with urokinase-type plasminogen activator (u-PA) being a key mediator.
• Previous research indicated that PMN's u-PA activity is contingent upon the presence of plasma.

Purpose of the Study:

• To elucidate the mechanism by which plasma influences PMN's role in fibrinolysis.
• To identify the specific plasma factors responsible for modulating PMN activity in thrombus resolution.

Main Methods:

• Investigated the degradation of various fibrinolytic components (scu-PA, tcu-PA, t-PA, plasmin) by PMN.
• Assessed the protective effect of plasma against PMN-mediated degradation.
• Identified specific plasma inhibitors, such as alpha1-antitrypsin.
• Utilized purified human neutrophil elastase to mimic PMN protease activity and tested neutralization by plasma inhibitors.

Main Results:

• PMN were shown to degrade scu-PA, tcu-PA, t-PA, and plasmin, leading to a loss of fibrinolytic activity.
• Plasma was found to protect these fibrinolytic components from PMN-mediated degradation.
• Alpha1-antitrypsin was identified as a significant protective factor within plasma.
• Purified human neutrophil elastase exhibited similar degradation effects to PMN, which were also neutralized by plasma inhibitors.

Conclusions:

• PMN possess a dual role in thrombus breakdown: they provide pro-fibrinolytic u-PA and also anti-fibrinolytic proteases like elastase.
• Plasma potentiates fibrinolysis by neutralizing PMN-derived elastase and inhibiting other fibrinolytic proteases.
• The anti-fibrinolytic function of PMN, when not counteracted by plasma, may be relevant in pathologies characterized by persistent fibrin deposition.