title: Topical application of phosphatidyl-inositol-3,5-bisphosphate for acute lung injury in neonatal swine.
abstract: Hypoxemic respiratory failure of the neonatal organism involves increased acid sphingomyelinase (aSMase) activity and production of ceramide, a second messenger of a pro-inflammatory pathway that promotes increased vascular permeability, surfactant alterations and alveolar epithelial apoptosis. We comparatively assessed the benefits of topical aSMase inhibition by either imipramine (Imi) or phosphatidylinositol-3,5-bisphosphate (PIP2) when administered into the airways together with surfactant (S) for fortification. In this translational study, a triple-hit acute lung injury model was used that entails repeated airway lavage, injurious ventilation and tracheal lipopolysaccharide instillation in newborn piglets subject to mechanical ventilation for 72 hrs. After randomization, we administered an air bolus (control), S, S+Imi, or S+PIP2. Only in the latter two groups we observed significantly improved oxygenation and ventilation, dynamic compliance and pulmonary oedema. S+Imi caused systemic aSMase suppression and ceramide reduction, whereas the S+PIP2 effect remained compartmentalized in the airways because of the molecule's bulky structure. The surfactant surface tensions improved by S+Imi and S+PIP2 interventions, but only to a minor extent by S alone. S+PIP2 inhibited the migration of monocyte-derived macrophages and granulocytes into airways by the reduction of CD14/CD18 expression on cell membranes and the expression of epidermal growth factors (amphiregulin and TGF-β1) and interleukin-6 as pro-fibrotic factors. Finally we observed reduced alveolar epithelial apoptosis, which was most apparent in S+PIP2 lungs. Exogenous surfactant "fortified" by PIP2, a naturally occurring surfactant component, improves lung function by topical suppression of aSMase, providing a potential treatment concept for neonates with hypoxemic respiratory failure.
authors.affiliation: Universitätsklinikum Schleswig-Holstein, Campus Kiel, Department of Pediatrics, Kiel, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Preuss
authors.forename: Friede D
authors.initials: FD
authors.lastname: Omam
authors.forename: Julia
authors.initials: J
authors.lastname: Scheiermann
authors.forename: Sabrina
authors.initials: S
authors.lastname: Stadelmann
authors.forename: Supandi
authors.initials: S
authors.lastname: Winoto-Morbach
authors.forename: Philipp
authors.initials: P
authors.lastname: von Bismarck
authors.forename: Sabine
authors.initials: S
authors.lastname: Adam-Klages
authors.forename: Friederike
authors.initials: F
authors.lastname: Knerlich-Lukoschus
authors.forename: Dennis
authors.initials: D
authors.lastname: Lex
authors.forename: Daniela
authors.initials: D
authors.lastname: Wesch
authors.forename: Janka
authors.initials: J
authors.lastname: Held-Feindt
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlig
authors.forename: Stefan
authors.initials: S
authors.lastname: Schütze
authors.forename: Martin F
authors.initials: MF
authors.lastname: Krause
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000473:pathology; D000287:Administration, Topical; D066258:Amphiregulin; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018821:CD18 Antigens / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D007099:Imipramine / Q000008:administration & dosage; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000008:administration & dosage*; D011663:Pulmonary Surfactants; D012121:Respiration, Artificial; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors; D013552:Swine; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D066258:Amphiregulin; D018821:CD18 Antigens; D002518:Ceramides; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D018129:Phosphatidylinositol Phosphates; D011663:Pulmonary Surfactants; D016212:Transforming Growth Factor beta; C106336:phosphatidylinositol 3,5-diphosphate; D013108:Sphingomyelin Phosphodiesterase; D007099:Imipramine