In order to evaluate further the physiological and inflammatory changes of meconium aspiration syndrome (MAS), 25 newborn piglets (1-2 days old, 1.5 +/- 0.4 kg) were studied. Piglets were briefly ventilated with 100% oxygen and then received an intratracheal bolus of 3 mL/kg of a 20% suspension of human meconium. They were then further ventilated, keeping PaCO2 at approximately 40 torr and PaCO2 at 70 torr during 4, 12, 24, and 48 h studies. Pulmonary function studies and tracheal aspirates were obtained at time zero and serially throughout the study. Bronchoalveolar lavage was performed at the end of the study to examine endogenous surfactant function. Control piglets received 3 mL/kg of intratracheal saline and were then ventilated for 48 h at an inspired oxygen concentration and mean airway pressure matched to the meconium treated group (to control for the effects of hyperoxia and barotrauma on the lung). MAS caused acute decreases in gas exchange and dynamic lung compliance, which returned toward baseline by 48 h (P < 0.001, ANOVA). Tracheal aspirate absolute neutrophil count, neutrophil chemotactic activity, albumin, and total protein concentrations also increased significantly over time (P < 0.001). Endogenous surfactant function appeared to be significantly inhibited by the meconium. All variables of lung injury were significantly higher in the meconium group compared to the saline control group over the 48 h study. Newborn piglets provide a clinically relevant model of MAS, demonstrating physiological and inflammatory changes with apparent alterations in endogenous surfactant function. Effective therapies for MAS may require interventions directed at all of these components of lung injury.