Topical application of phosphatidyl‐inositol‐3,5‐bisphosphate for acute lung injury in neonatal swine

Journal of Cellular and Molecular Medicine

Stefanie Preuß⁴  Friede D. Omam⁴  Julia Scheiermann⁴  Sabrina Stadelmann⁴  Supandi Winoto-Morbach¹  Philipp von Bismarck⁴  Sabine Adam-Klages¹  Friederike Knerlich-Lukoschus²  Dennis Lex³  Daniela Wesch¹  Janka Held-Feindt²  Stefan Uhlig³  Stefan Schütze¹ 

[1] Universitätsklinikum Schleswig-Holstein, Campus Kiel, Institute of Immunology, Kiel, Germany;Universitätsklinikum Schleswig-Holstein, Campus Kiel, Department of Neurosurgery, Kiel, Germany;Universitätsklinikum, RWTH Aachen, Institute of Pharmacology and Toxicology, Aachen, Germany;Universitätsklinikum Schleswig-Holstein, Campus Kiel, Department of Pediatrics, Kiel, Germany

关键词: apoptosis;    ceramide;    macrophages;    epithelial growth factors;    fibrosis;   

DOI  :  10.1111/j.1582-4934.2012.01618.x

来源: Wiley

【 摘 要 】

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.

【 授权许可】

Unknown   
© 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd