Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation

Area of Science:

• Immunology
• Cardiovascular Science
• Biochemistry

Background:

• Complement activation is a key inflammatory response during cardiopulmonary bypass (CPB).
• The specific roles of early (C3a) versus terminal (C5a, C5b-9) complement components in CPB-induced cellular activation remain unclear.
• Leukocyte and platelet activation are significant cellular events during CPB.

Purpose of the Study:

• To investigate the distinct contributions of early and terminal complement components to CPB-induced leukocyte and platelet activation.
• To evaluate the therapeutic potential of targeting the C5 complement component in a simulated extracorporeal circulation model.

Main Methods:

• Utilized a simulated extracorporeal circulation model to induce complement activation.
• Administered a blocking monoclonal antibody (mAb) against human C5 to assess its impact on complement and cellular activation markers.
• Measured complement components (C3a, C5a, C5b-9), serum hemolytic activity, neutrophil CD11b expression, P-selectin on platelets, and leukocyte-platelet conjugates.

Main Results:

• Simulated CPB activated complement (C3a, C5a, C5b-9), platelets (P-selectin, conjugates), and neutrophils (CD11b).
• Anti-C5 mAb inhibited C5a, C5b-9 generation, and hemolytic activity but did not affect C3a.
• Anti-C5 mAb significantly reduced neutrophil CD11b upregulation and abolished platelet activation markers (P-selectin, conjugates).

Conclusions:

• Terminal complement components C5a and C5b-9, not C3a, directly mediate platelet and neutrophil activation during extracorporeal circulation.
• The C5 complement component represents a promising therapeutic target to mitigate CPB-induced inflammation and cellular activation.