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.

Inhibition of acid sphingomyelinase by tricyclic antidepressants and analogons

“…The addition of imipramine to the exogenous surfactant improved lung function and decreased leukocyte counts and interleukin concentrations in the lavage fluid (Von Bismarck et al, 2008 ). In a follow-up study, Preuss and co-workers also demonstrated that topical Asm inhibition by imipramine significantly improves several respiratory parameters and lung edema in a triple-hit lung injury model (Preuss et al, 2012 ). Taken together, these studies make a strong argument for the use of surfactant preparations fortified with an ASM inhibitor for the treatment of neonates with hypoxemic respiratory failure.…”

Secretory sphingomyelinase in health and disease

“…The authors speculate that, due to the high abundance of S-ASM from endothelial cells, injured lung capillary endothelial cells aggravate cellular damage in a vicious cycle, resulting in the sustained lung damage observed in patients despite smoking cessation. In a neonatal pigled model of pulmonary inflammation, S-ASM activity and ceramide concentration are reduced in serum after treatment of lungs with inhaled surfactant factor combined with the FIASMA imipramine (von Bismarck et al, 2008;Preuß et al, 2012).…”

Inflammatory Mediators in Tracheal Aspirates of Preterm Infants Participating in a Randomized Trial of Inhaled Nitric Oxide

“…Furthermore, acid sphingomyelinase (ASM), an enzyme generating ceramide, was increased in ovine BPD [25] and in septic patients, where it correlated with their mortality [26]. These findings are remarkable, because the ASM pathway is critical for edema formation in many models of acute lung injury [27] including neonatal piglet models [28,29] and may also promote apoptosis in lung epithelial cells [30,31]. …”