Meconium is a potent activator of complement in human serum and in piglets.
Meconium aspiration syndrome (MAS) is a clinical condition in the newborn infant with a significant morbidity and mortality. The complex pathophysiology of MAS, leading to both pulmonary and systemic complications, is characterized by an incompletely understood inflammatory reaction. Treatment is symptomatic, mainly limited to airway cleaning and ventilatory support. In this study, we show for the first time that meconium is a potent activator of complement, a key mediator of inflammation. In vitro, meconium activated the alternative complement pathway in human umbilical cord serum as judged by a substantial increase in the alternative pathway convertase C3bBbP. The activation proceeded through C3 (C3bc) and the terminal C5-9 pathway (terminal SC5b-9 complement complex), whereas the classical and lectin pathways were not activated (C1rs-C1-inhibitor complexes and C4bc). The lipid fraction, containing, e.g. free fatty acids, and the water fraction, containing, e.g. bile acids, contributed equally to the complement activation. A blocking antibody to factor D (alternative pathway) completely inhibited the meconium-induced complement activation, whereas blocking antibodies to mannose-binding lectin (lectin pathway) and C2 (classical and lectin pathway) had no effect. In vivo, meconium induced systemic complement activation in a piglet model of MAS, paralleling the increase in lung dysfunction. In conclusion, meconium is a potent activator of the complement system both in vitro and in vivo. Complement may be important in the pathogenesis of MAS, and specific complement inhibition might be a possible treatment approach in MAS.
Castellheim
Albert
A
Department of Pediatric Research, Rikshospitalet University Hospital, Oslo 0027, Norway. albert.castellheim@klinmed.uio.no
Lindenskov
Paal H H
PH
Pharo
Anne
A
Fung
Michael
M
Saugstad
Ola D
OD
Mollnes
Tom E
TE
D000367:Age Factors; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology*; D003172:Complement C1 / Q000378:metabolism; D016264:Dextran Sulfate / Q000494:pharmacology; D005260:Female; D005312:Fetal Blood / Q000276:immunology; D006801:Humans; D007231:Infant, Newborn; D008070:Lipopolysaccharides / Q000494:pharmacology; D008470:Meconium / Q000276:immunology*; D008471:Meconium Aspiration Syndrome / Q000276:immunology*; D011247:Pregnancy; D044967:Serum / Q000276:immunology; D012709:Serum Albumin / Q000494:pharmacology; D013552:Swine
D000925:Anticoagulants; D003172:Complement C1; D008070:Lipopolysaccharides; D012709:Serum Albumin; D016264:Dextran Sulfate