22 New Anti-Inflammatory Therapy for Neonatal Acute Lung Injury: Varespladib (A-001) Inhibits Ex-Vivo Secretory Phospholipase

Abstract

Background: Secretory phospholipase A2(sPLA2) is crucial for surfactant catabolism and inflammation. We demonstrated high sPLA2 activity during infection related respiratory failure (IRRF), hyaline membrane disease (iRDS), RSV-triggered ARDS. sPLA2 is also responsible for lung damage during meconium aspiration syndrome (MAS). Varespladib is the first new anti-inflammatory drug able to directly inhibit sPLA2 and it resulted efficacious in animals and promising in adults.Aim: To test varespladib efficacy in an ex-vivo model of direct endotracheal administration in various types of neonatal acute lung injury.Methods: 24 neonates affected by iRDS, 12 with IRRF, 5 with MAS have been subjected to non-bronchoscopic broncho-alveolar lavage according to European Respiratory Society advices. Supernatant has been subdivided in aliquots which have been added with various concentrations of varespladib or equivalent volumes of saline. Real time sPLA2 activity and total protein content have been measured. Enzyme activity has been corrected for dilutional factors and varespladib absorbance. Clinical data were registered up to the intensive care unit discharge.Results: Varespladib reduces sPLA2 during iRDS(-20%; p< 0.0001), MAS(-23%; p=0.04), IRRF(- 15%; p=0.003). Varespladib efficacy is higher when a lower capillary extravasation is present (ratio sPLA2 activity reduction/total proteins = 2.17 in iRDS; 0.59 in IRRF, 0.53 in MAS). IC50 has been calculated and varespladib efficacy correlates with the basal enzyme activity (rho= 0.375; p=0.017). No correlations with gestational age, birth weight, surfactant cumulative need, mechanical ventilation and oxygen therapy duration were found.Conclusions: Varespladib efficaciously inhibits sPLA2 in an ex-vivo model of direct administration. This might have important anti-inflammatory effects and spare surfactant from its catabolism.