Rationale: In acute inflammatory lung disease in newborn infants, exogenous surfactant only transiently improves lung function. We hypothesized that the transient nature of this protection is in part explained by elevated acid-sphingomyelinase (a-SMase) activity that may inactivate surfactant and promote pro-inflammatory responses. Objective: We investigated the intermediate-term effects (>12h) of a-SMase inhibition in a neonatal piglet model of repeated airway lavage by the intratracheal use of the a-SMase inhibitor imipramine, together with exogenous surfactant as a carrier substance. Methods: After surfactant washout and induction of pulmonary inflammation, lung function was monitored over 24h of mechanical ventilation and followed by ex vivo analyses. In addition, we studied the effect of lipopolysachharide inhalation in a-SMase deficient mice at 48h. Measurements and main results: Surfactant washout increased both pulmonary a-SMase activity and ceramide content; this was attenuated by surfactant and prevented in the surfactant+imipramine group. Compared with surfactant alone, PaO₂, dynamic compliance, and extra-vascular lung water were improved in the final 12h in the surfactant+imipramine group. At 24h, lavage fluid leukocyte counts and IL-8 concentrations decreased, and physical surfactant film properties improved. In the mouse model at 48h, a-SMase deficient mice showed reduced pulmonary ceramide levels and attenuated leukocyte influx into the alveolar space. Conclusion: We conclude that stabilization of exogenous surfactant by adding imipramine to create a "fortified surfactant preparation" improves lung function in a clinically relevant piglet model, and that this effect can be attributed to the inhibition of a-SMase as evidenced in the mouse model.