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.

Alveolar lipids in pulmonary disease. A review

“…BAL phosphatidylglycerol was also decreased in ARDS with increased BAL surface tension [69]. Experimental supplementation with phosphatidylglycerol in a neonatal piglet ARDS model reduced IL-6 and alveolar apoptosis, and preserved the alveolar-capillary barrier, thus decreasing pulmonary edema [248].…”

Crosstalk Between Acid Sphingomyelinase and Inflammasome Signaling and Their Emerging Roles in Tissue Injury and Fibrosis

“…The pharmacological inhibitor CA-074Me prevents the inflammasome signaling activating and the IL-1β production upon exposure to α-toxin (Ma et al, 2017). Besides, the mature form of cathepsin D follows the ceramide production pattern (Spengler et al, 2018). A bacterial extract of Lactobacillus casei cell wall fragments (LCWE), induces the formation of the NLRP3 inflammasome and colocalization of NLRP3 with ASC or caspase-1.…”

“…Acid sphingomyelinase-ceramide system acts as key players in a piglet acute respiratory distress syndrome (ARDS) model (Spengler et al, 2018). Inositol 1,2,6-trisphosphate (IP3) and phosphatidylinositol 3,5-bisphosphate (PIP2) significantly reduce pulmonary edema and increase the oxygenation index as well as ventilation index by suppressing ASM and ASMdependent ceramide production, which are further connected to inhibition of NLRP3-ASC-caspase-1 axis.…”

Role of inositol to improve surfactant functions and reduce IL-6 levels: A potential adjuvant strategy for SARS-CoV-2 pneumonia?

“…On the one hand, the change in signal transducer and activator of transcription 3 (STAT3) phosphorylation could reduce macrophage recruitment and their phenotype switching, with consequent reduction of IL-6-producing cell population [72] . On the other hand, the fine-regulated cross-talk between IL-6-mediated pathways and surfactant-derived phosphatidylglycerol subfractions may account for the return to the homeostasis in the bronchoalveolar microenvironment [73] , [74] , [75] .…”