Mechanisms of complement activation and effects of C1-inhibitor on the meconium-induced inflammatory reaction in human cord blood

作者：Salvesen Bodil^*; Nielsen Erik W; Harboe Morten; Saugstad Ola D; Mollnes Tom E

来源：Molecular Immunology, 2009, 46(4): 688-694.

DOI：10.1016/j.molimm.2008.09.001

• C1-inhibitor
• Complement system
• Cord blood
• Cytokines
• Inflammation
• Meconium

Background: Meconium aspiration syndrome has a complex pathophysiology. Meconium activates the complement system and meconium-induced cytokine formation is differentially mediated by complement and CD14. Cl-inhibitor (C1-INH) regulates complement and contact-system activation mainly by protease inhibition, but may reduce inflammation by other mechanisms as well.
Objective: The aim of the study was to investigate the initial mechanisms of meconium-induced complement activation and to study the effect of C1-INH on the meconium-induced inflammatory reaction.
Methods: Human serum from five donors was preincubated with an anti-MBL monoclonal antibody and then incubated with meconium for 30 min at 37 degrees C. Human cord whole blood, anticoagulated with lepirudin, from six donors was preincubated with C1-INH and then incubated with meconium for 30 min and 4 h at 37 degrees C. Complement activation products specific for the different pathways were measured by ELISAs: classical pathway C1rs/C1-INH complexes, classical and lectin pathway C4d, alternative pathway C3bBbP, and terminal pathway sC5b-9 complex (TCC). A Bio-Plex Array Reader was used to measure 27 inflammatory mediators.
Results: The anti-MBL monoclonal antibody significantly reduced meconium-induced formation of C4d by 63% (p = 0.0159) and TCC by 27% (p = 0.0079). C1-INH dose-dependently inhibited meconium-induced formation of C1rs/C1-INH complexes, C4d, C3bBbP, and TCC compared to albumin (p < 0.002 for all). C1-INH induced a dose-dependent and substantial inhibition of meconium-induced formation of the proinflammatory cytokines TNF alpha, IL-1 beta, IL-6 and IFN-gamma (p < 0.01 for all), the chemokines IL-8, MCP-1, MIP-1 alpha, MIP-1 beta, and eotaxin (p < 0.02 for all), the growth factors G-CSF, GM-CSF, basic FGF, and PDGFbb (p < 0.05 for all), and the anti-inflammatory cytokine IL-1ra (p < 0.001).
Conclusions: Meconium activated the lectin complement pathway as well as the alternative pathway. C1-INH efficiently reduced a broad spectrum of inflammatory mediators even at the lowest concentration. Administration of C1-INH may thus reduce the inflammatory response in MAS.

• 出版日期2009-2