Does meconium cause meconium aspiration syndrome (MAS) or is meconium discharge only a marker of fetal hypoxia? This dispute has lasted for centuries, but since the 1960s, detrimental effects of meconium itself on the lungs have been demonstrated in animal experiments. In clinical MAS, persistent pulmonary hypertension of the newborn is the leading cause of death in MAS. Regarding the complex chemical composition of meconium, it is difficult to identify a single agent responsible for the pathophysiology. However, considering that meconium is stored in the intestines, partly unexposed to the immune system, aspirated meconium could be recognized as ‘danger', representing damaged self. The common denominator in the pathophysiology could therefore be activation of innate immunity. Thus, a bulk of evidence implies that meconium is a potent activator of inflammatory mediators, including cytokines, complement, prostaglandins and reactive oxygen species. We hypothesize that the two main recognition systems of innate immunity, the Toll-like receptors and the complement system, recognize meconium as ‘danger', which leads not only to lung dysfunction but also to a systemic inflammatory response. This might have therapeutic implications in the future.

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. The aspiration of meconium-stained amniotic fluid (MSAF) in the newborn can lead to meconium aspiration syndrome (MAS), which is a clinical syndrome with significant morbidity and mortality (1). MAS might be defined as respiratory distress in an infant who is born through MSAF and whose symptoms cannot be otherwise explained (2). The pathophysiology of lung injury in MAS is complex and includes both mechanical obstruction by meconium and pronounced inflammatory responses (3). It has been postulated that other conditions, including intrauterine infection and chronic and acute asphyxia, rather than inhaled meconium, may explain the primary pathology of MAS (4). The pathophysiology of MAS (hypoxemia, pulmonary inflammation, and disturbed pulmonary vasoregulation) bears similarities with acute respiratory distress syndrome (5), the latter frequently being a manifestation of the systemic inflammatory response syndrome (SIRS) in the presence or absence of bacterial infection (6, 7).Lung inflammation by itself can lead to systemic inflammation (8). Leakage of meconium content through the alveolar wall to the lung capillaries may bring substances from meconium in direct contact with blood, leading to systemic inflammation. Furthermore, lung rupture and meconium embolism in chronic intrauterine meconium aspiration has been described (9), which may be an additional mechanism for meconium exposure to blood...

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 Ͻ 0.0005). The increase in TCC correlated with lung dysfunction: closely with oxygenation index (r ϭ 0.51, p Ͻ 0.0001) and ventilation index (r ϭ 0.64, p Ͻ 0.0001) and inversely with lung compliance (r ϭ Ϫ0.22, p ϭ 0.05). IL-1␤ and tumor necrosis factor-␣ increased significantly in MAS animals compared with the controls (p ϭ 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 ϭ 0.32). Finally, the subgroup of MAS animals that died (n ϭ 5) had substantially higher TCC concentration compared with the surviving MAS animals (n ϭ 7; p Ͻ 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. Intrauterine passage of meconium has for centuries been interpreted as a sign of perinatal death or suppression of placental function (7). Since the 1970s, there has been a growing body of evidence suggesting detrimental effects of meconium on newborn lungs, and therapeutic suctioning of the airways to clear meconium therefore was established routinely (11,12). Intratracheal suction should be performed only in selective cases (13). The role of meconium per se in the pathophysiology of MAS is still debated (14) and has been questioned by Katz and Bowes (4), claiming that antenatal asphyxia leading to persistent pulmonary hypertension could cause the lung injury, leaving a minor role to direct effects mediated by meconium.In clinical medicine, the diversity between MSAF and MAS may be due to several meconium-related factors, such as different amounts being aspirated (15), composition (16 -18) and consistency (19) of meconium, intrauterine effects of meconium (4,20), and severity and duration of accompanying asphyxia (4). In the experimental model used in the present study (21), most of these factors can be standardized. Still, in previous experiments using the same model with higher doses of meconium, we have observed a substantial interanimal variation in morbidity and mortality, leading us to speculate that various host factors could be related to the severity of the inflammation triggered by meconium.

No abstract

The pathophysiology of meconium aspiration syndrome (MAS) is complex. We recently showed that meconium is a potent activator of complement. In the present study, we investigated whether the complement activation occurring in experimental MAS is associated with a systemic inflammatory response as judged by granulocyte activation and cytokine and chemokine release. MAS was induced by the instillation of meconium into the lungs of newborn piglets (n ¼ 8). Control animals (n ¼ 5) received saline under otherwise identical conditions. Haemodynamic and lung dynamic data were recorded. Complement activation, revealed by the terminal sC5b-9 complex (TCC), and cytokines [interleukin (IL)-6 and IL-8] were measured in plasma samples by enzyme immunoassays. The expression of CD18, CD11b and oxidative burst in granulocytes was measured in whole blood by flow cytometry. Plasma TCC increased rapidly in the MAS animals in contrast with controls (P < 0.0005). The TCC concentration correlated closely with oxygenation index (r ¼ 0.48, P < 0.0005) and ventilation index (r ¼ 0.57, P < 0.0005) and inversely with lung compliance (r ¼ À0.63, P < 0.0005). IL-6 and IL-8 increased in MAS animals compared with the controls (P ¼ 0.002 and P < 0.001, respectively). Granulocyte oxidative burst declined significantly in the MAS animals compared with the controls (P < 0.02). TCC correlated significantly with IL-6 (r ¼ 0.64, P < 0.0005) and IL-8 (r ¼ 0.32; P ¼ 0.03) and inversely with oxidative burst (r ¼ À0.37; P ¼ 0.02). A systemic inflammatory response associated with complement activation is seen in experimental MAS. This reaction may contribute to the pathogenesis of MAS.