Improved pulmonary function by acid sphingomyelinase inhibition in a newborn piglet lavage model.
BACKGROUND
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.


OBJECTIVE
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.


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(O(2)), 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.
von Bismarck
Philipp
P
Department of Pediatrics, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Schwanenweg 20, 24105 Kiel, Germany.
Wistädt
Carlos-Francisco García
CF
Klemm
Karsten
K
Winoto-Morbach
Supandi
S
Uhlig
Ulrike
U
Schütze
Stefan
S
Adam
Dieter
D
Lachmann
Burkhard
B
Uhlig
Stefan
S
Krause
Martin F
MF
D000818:Animals; D000831:Animals, Newborn; D018893:Bronchoalveolar Lavage; D002518:Ceramides / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D007099:Imipramine / Q000627:therapeutic use*; D008170:Lung Compliance / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011654:Pulmonary Edema / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D011659:Pulmonary Gas Exchange / Q000502:physiology*; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors*; D013552:Swine; D013997:Time Factors
D002518:Ceramides; D004791:Enzyme Inhibitors; D013108:Sphingomyelin Phosphodiesterase; D007099:Imipramine