title: Improved pulmonary function by acid sphingomyelinase inhibition in a newborn piglet lavage model.
abstract: 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.
authors.affiliation: Department of Pediatrics, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Schwanenweg 20, 24105 Kiel, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: von Bismarck
authors.forename: Carlos-Francisco García
authors.initials: CF
authors.lastname: Wistädt
authors.forename: Karsten
authors.initials: K
authors.lastname: Klemm
authors.forename: Supandi
authors.initials: S
authors.lastname: Winoto-Morbach
authors.forename: Ulrike
authors.initials: U
authors.lastname: Uhlig
authors.forename: Stefan
authors.initials: S
authors.lastname: Schütze
authors.forename: Dieter
authors.initials: D
authors.lastname: Adam
authors.forename: Burkhard
authors.initials: B
authors.lastname: Lachmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlig
authors.forename: Martin F
authors.initials: MF
authors.lastname: Krause
mesh_terms: 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
chemical_list: D002518:Ceramides; D004791:Enzyme Inhibitors; D013108:Sphingomyelin Phosphodiesterase; D007099:Imipramine