Aspiration of meconium produces an inflammatory reaction resulting in necrotic changes in lung tissue. To further investigate the mechanisms of the meconium-induced early pulmonary injury, twenty 10-12-d-old piglets were studied for lung tissue ultrastructural and apoptotic changes and phospholipase A2 activity. Twelve piglets received an intratracheal bolus (3 mL/kg) of a 20-mg/mL (thin, n = 6) or 65-mg/mL (thick, n = 6) mixture of human meconium, and control piglets (n = 5) received the same amount of intratracheal saline. Three ventilated piglets with no aspiration were also studied. Pulmonary hemodynamics and systemic oxygenation were followed for 6 h after meconium or saline insufflation. In the control groups, the pulmonary tissue showed open alveolar spaces and intact vascular walls, whereas meconium administration resulted in severe pneumonitis, with alveolar spaces filled with inflammatory exudate. Meconium instillation additionally resulted in edematous changes in the vascular walls and alveolar epithelium, whereas type II pneumocytes were intact. The amount of apoptotic cells was increased, especially in the respiratory epithelium, and the catalytic activity of phospholipase A2 in lung tissue samples was significantly elevated after thick meconium instillation. This activity rise proved to be mainly because of human group I phospholipase A2, introduced by meconium. Our data thus show that aspiration of meconium leads to severe lung tissue inflammation with early ultrastructural changes in the pulmonary alveolar walls and is associated with apoptotic cell death in the epithelium, already during the first hours after the insult. These results further suggest that high phospholipase A2 activity, mainly introduced into the lungs within the meconium, may have an important role in the initiation of these alterations in neonatal lungs.

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Acute lung injury induced by meconium aspiration is characterized by rapidly developing pulmonary inflammation with influx of activated polymorphonuclear cells. To evaluate the role of meconium in the activation of these invading cells, we described the oxidative capacity of circulating neutrophils after intratracheal administration of thick human meconium in pigs. We also examined the direct effects of varying meconium concentrations on the oxidative burst of human neutrophils in vitro. In neutrophils isolated from meconium-insufflated pigs, phorbol myristate acetate stimulation led to an average 11.7-fold increase in production of reactive oxygen species, measured by chemiluminescence, whereas the increase in control cells from saline-instilled pigs was only 3.1-fold, p =.012 between the groups. Activation of unstimulated human leukocytes by meconium resulted in a dose-dependent response. The lowest meconium concentration (0.2 mg/mL) had an inhibitory effect on neutrophil activation, whereas higher concentrations of meconium (1 and 2 mg/mL) increased neutrophil oxygen radical production progressively. These results thus indicate that moderate and high concentrations of aspirated meconium rapidly activate circulating neutrophils with a resulting oxidative burst contributing to pulmonary tissue injury, whereas low contamination of the aspirated material may in fact suppress the development of oxidative lung injury.

Severe perinatal aspiration of meconium is frequently complicated by unsuccessful neonatal adaptation with associated pulmonary hypertension. This vascular complication is supposedly related to pulmonary release of vasoconstrictory agents, including metabolites of arachidonic acid. Thus, to investigate the role of prostanoids on these meconium-induced circulatory changes in the lungs, the hemodynamic response to meconium instillation was studied in acetylsalicylic acid-pretreated juvenile pigs. Twelve 10-wk-old pigs with adapted lung circulation received 3 mL/kg of 65 mg/mL human meconium via the endotracheal tube. Six of them were medicated with 10 mg/kg acetylsalicylic acid 30 min before meconium insufflation. Hemodynamic parameters and urinary excretion of stable metabolites of thromboxane A2 and prostacyclin were measured serially for 6 h after the insult. Meconium administration induced a biphasic increase in mean pulmonary artery pressure and pulmonary vascular resistance, and a rapid rise in urinary levels of prostanoid metabolites. Acetylsalicylic acid pretreatment prevented the initial (0-1 h) pulmonary hypertensive response and increase in prostanoid excretion. During the second phase (1-6 h), acetylsalicylic acid did not attenuate the progressive increase in mean pulmonary artery pressure and pulmonary vascular resistance nor did it affect the longitudinal distribution of the pulmonary resistances. Our results thus show that in adapted porcine lungs, arachidonic acid metabolites contribute to the early hypertensive response, but have only minor effects during the second phase vascular hypertension.