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Improved Pulmonary Function by Acid Sphingomyelinase Inhibition in a Newborn Piglet Lavage Model

¹ Department of Pediatrics and ² Institute of Immunology, Universitätsklinikum Schleswig-Holstein, Kiel, Germany; ³ Institute of Pharmacology and Toxicology, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany; and ⁴ Department of Anesthesiology, Erasmus University Medical Center, Rotterdam, The Netherlands

Correspondence and requests for reprints should be addressed to Martin F. Krause, M.D., Department of Pediatrics, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Schwanenweg 20, 24105 Kiel, Germany. E-mail: m.krause{at}pediatrics.uni-kiel.de

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 proinflammatory responses.

Objectives: We investigated the intermediate-term effects (>12 h) 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 24 hours of mechanical ventilation and followed by ex vivo analyses. In addition, we studied the effect of lipopolysaccharide inhalation in a-SMase–deficient mice at 48 hours.

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 plus imipramine group. Compared with surfactant alone, Pa_O2, dynamic compliance, and extravascular lung water were improved in the final 12 hours in the surfactant plus imipramine group. At 24 hours, lavage fluid leukocyte counts and IL-8 concentrations decreased, and physical surfactant film properties improved. In the mouse model at 48 hours, a-SMase–deficient mice showed reduced pulmonary ceramide levels and attenuated leukocyte influx into the alveolar space.

Conclusions: 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.

Key Words: acute neonatal inflammatory lung injury • ceramide • imipramine • surfactant • acid sphingomyelinase–deficient mice

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Ceramide is generated by acid sphingomyelinase in pulmonary cells and contributes to impaired physical surfactant film properties. What This Study Adds to the Field The nonspecific acid sphingomyelinase inhibitor imipramine reduces ceramide generation by intratracheal application and causes intermediate-term improvements in lung function in a neonatal piglet model of acute lung injury.

 

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