Meconium Is A Potent Activator of Complement in Human Serum and in Piglets

Department of Pediatric Research, Rikshospitalet University Hospital, Oslo 0027, Norway.
Pediatric Research (Impact Factor: 2.31). 03/2004; 55(2):310-8. DOI: 10.1203/01.PDR.0000100902.76021.8E
Source: PubMed


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.

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Available from: Anne Pharo, May 20, 2014
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    • "In utero hypoxia leading to relaxation of the anal sphincter has been considered a reason for meconium passage. Adverse intrauterine environment compromising fetal well-being can lead to MSAF (Castellheim et al. 2004; Mollnes et al. 2008; Berkus et al. 1994). "
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    ABSTRACT: Meconium aspiration syndrome (MAS) is a serious condition in newborns, associated with a poorly characterized inflammatory reaction. The aim of this study was to investigate a possible role for complement in pulmonary pathophysiology and systemic inflammation in experimental MAS. MAS was induced by instillation of meconium into the lungs of 12 hypoxic piglets. Six controls received saline under otherwise identical conditions. Hemo- and lung dynamics were recorded for 5 h. Plasma complement activation, revealed by the terminal sC5b-9 complex (TCC), and cytokines were measured by enzyme immunoassays. TCC increased substantially in MAS animals compared with controls (p <0.0005). The increase in TCC correlated with lung dysfunction: closely with oxygenation index (r=0.51, p <0.0001) and ventilation index (r=0.64, p < 0.0001) and inversely with lung compliance (r=-0.22, p=0.05). IL-1beta and tumor necrosis factor-alpha increased significantly in MAS animals compared with the controls (p=0.004 and 0.008, respectively). The cytokine increase occurred later than TCC and showed correlations with lung dysfunction similar to TCC. IL-10 did not discriminate between MAS animals and controls (p=0.32). Finally, the subgroup of MAS animals that died (n=5) had substantially higher TCC concentration compared with the surviving MAS animals (n=7; p <0.0005). TCC increased substantially in MAS and was closely correlated to lung dysfunction. Complement activation preceded cytokine release, which may suggest a primary role for complement in the pathophysiology of MAS.
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    ABSTRACT: An important feature of meconium-instilled newborn lungs is an inflammatory response and apoptotic cell death. It was recently demonstrated by our group and supported by several other investigators in a relatively short period of time. Apoptosis exists also in healthy lungs, but in meconium-instilled lungs its level is usually dramatically higher. Apoptosis is characterized by loss of cell function, decrease in cell size, and its morphology. Apoptosis plays an important role in normal cell life, but increased levels of apoptosis induce great damage for any tissues. Apoptosis in the lungs has been greatly overlooked for the past decade, and meconium-induced apoptosis is a relatively new event and not effectively studied at the present time. This Review summarized current knowledge regarding meconium-induced inflammation and apoptosis in newborn lungs.
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