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.
Highlights
Hypoxemic respiratory failure of the neonate is a life-threatening manifestation of neonatal acute lung injury that is defined as severely impaired lung function involving reduced lung compliance, permeability oedema, increased surfactant surface tension, transpul
A summary of treatment effects is provided in Table 2 and proves the superiority of S+PIP2 treatment for all four parameters when compared to S alone
That the low aSMase concentrations found in the BALF of S+PIP2-treated piglets (Fig. 7C) essentially inhibited migration of granulocytes and monocyte-derived macrophages into the airspaces [38], suppressed their metabolic activity [39] and modulated the epithelial inflammatory response [36, 40] (“epithelial hypothesis”)
Summary
Hypoxemic respiratory failure of the neonate is a life-threatening manifestation of neonatal acute lung injury (nALI) that is defined as severely impaired lung function involving reduced lung compliance, permeability oedema, increased surfactant surface tension, transpul-. In nALI models, the physical properties of surfactant films are impaired by increased concentrations of the phospholipid ceramide [1, 2]. Ceramide inhibits the synthesis of dipalmitoyl- phosphatidylcholine (DPPC) by inhibiting the key enzyme cholinephosphate cytidylyltransferase [3]. The addition of ceramide to surfactant increases the surface tension of surfactant films in a dose-dependent manner [4]. Ceramide augments permeability oedema which further contributes to surfactant dysfunction [5]. Ceramide mediates caspase-dependent [6] apoptosis, as evidenced in lung fibroblasts and airway epithelial cells [7]
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