Novel therapeutic roles for surfactant-inositols and -phosphatidylglycerols in a neonatal piglet ARDS model: a translational study.

Abstract

The biological and immune-protective properties of surfactant-derived phospholipids and phospholipid subfractions in the context of neonatal inflammatory lung disease are widely unknown. Using a porcine neonatal triple-hit acute respiratory distress syndrome (ARDS) model (repeated airway lavage, overventilation, and LPS instillation into airways), we assessed whether the supplementation of surfactant (S; poractant alfa) with inositol derivatives [inositol 1,2,6-trisphosphate (IP3) or phosphatidylinositol 3,5-bisphosphate (PIP2)] or phosphatidylglycerol subfractions [16:0/18:1-palmitoyloleoyl-phosphatidylglycerol (POPG) or 18:1/18:1-dioleoyl-phosphatidylglycerol (DOPG)] would result in improved clinical parameters and sought to characterize changes in key inflammatory pathways behind these improvements. Within 72 h of mechanical ventilation, the oxygenation index (S+IP3, S+PIP2, and S+POPG), the ventilation efficiency index (S+IP3 and S+POPG), the compliance (S+IP3 and S+POPG) and resistance (S+POPG) of the respiratory system, and the extravascular lung water index (S+IP3 and S+POPG) significantly improved compared with S treatment alone. The inositol derivatives (mainly S+IP3) exerted their actions by suppressing acid sphingomyelinase activity and dependent ceramide production, linked with the suppression of the inflammasome nucleotide-binding domain, leucine-rich repeat-containing protein-3 (NLRP3)-apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-caspase-1 complex, and the profibrotic response represented by the cytokines transforming growth factor-β1 and IFN-γ, matrix metalloproteinase (MMP)-1/8, and elastin. In addition, IκB kinase activity was significantly reduced. S+POPG and S+DOPG treatment inhibited polymorphonuclear leukocyte activity (MMP-8 and myeloperoxidase) and the production of interleukin-6, maintained alveolar-capillary barrier functions, and reduced alveolar epithelial cell apoptosis, all of which resulted in reduced pulmonary edema. S+DOPG also limited the profibrotic response. We conclude that highly concentrated inositol derivatives and phosphatidylglycerol subfractions in surfactant preparations mitigate key inflammatory pathways in inflammatory lung disease and that their clinical application may be of interest for future treatment of the acute exudative phase of neonatal ARDS.

• Authors: Dietmar Spengler, Supandi Winoto-Morbach, Sarah Kupsch, Christina Vock, Katharina Blöchle, Susanna Frank, Nele Rintz, Marie Diekötter, Harshavardhan Janga, Markus Weckmann, Sabine Fuchs, Andra B Schromm, Heinz Fehrenbach, Stefan Schütze, Martin F Krause
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 314 Issue 1 Pg. L32-L53 (01 01 2018) ISSN: 1522-1504 [Electronic] United States
• PMID: 28860142 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• NF-kappa B
• NLR Family, Pyrin Domain-Containing 3 Protein
• Phosphatidylglycerols
• Pulmonary Surfactants
• Vitamin B Complex
• Inositol

Topics

• Animals
• Animals, Newborn
• Apoptosis
• Bronchoalveolar Lavage Fluid
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Female
• Humans
• Inositol (pharmacology)
• Male
• NF-kappa B (genetics, metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, metabolism)
• Phosphatidylglycerols (pharmacology)
• Pulmonary Edema (drug therapy, metabolism, pathology)
• Pulmonary Gas Exchange
• Pulmonary Surfactants (pharmacology)
• Random Allocation
• Respiration, Artificial
• Respiratory Distress Syndrome, Newborn (drug therapy, metabolism, pathology)
• Swine
• Translational Research, Biomedical
• Vitamin B Complex (pharmacology)