The Synthetic Surfactant CHF5633 Restores Lung Function and Lung Architecture in Severe Acute Respiratory Distress Syndrome in Adult Rabbits.

PURPOSE: Acute respiratory distress syndrome (ARDS) is a major cause of hypoxemic respiratory failure in adults. In ARDS extensive inflammation and leakage of fluid into the alveoli lead to dysregulation of pulmonary surfactant metabolism and function. Altered surfactant synthesis, secretion, and breakdown contribute to the clinical features of decreased lung compliance and alveolar collapse. Lung function in ARDS could potentially be restored with surfactant replacement therapy, and synthetic surfactants with modified peptide analogues may better withstand inactivation in ARDS alveoli than natural surfactants. METHODS: This study aimed to investigate the activity in vitro and the bolus effect (200 mg phospholipids/kg) of synthetic surfactant CHF5633 with analogues of SP-B and SP-C, or natural surfactant Poractant alfa (Curosurf®, both preparations Chiesi Farmaceutici S.p.A.) in a severe ARDS model (the ratio of partial pressure arterial oxygen and fraction of inspired oxygen, P/F ratio ≤ 13.3 kPa) induced by hydrochloric acid instillation followed by injurious ventilation in adult New Zealand rabbits. The animals were ventilated for 4 h after surfactant treatment and the respiratory parameters, histological appearance of lung parenchyma and levels of inflammation, oxidative stress, surfactant dysfunction, and endothelial damage were evaluated. RESULTS: Both surfactant preparations yielded comparable improvements in lung function parameters, reductions in lung injury score, pro-inflammatory cytokines levels, and lung edema formation compared to untreated controls. CONCLUSIONS: This study indicates that surfactant replacement therapy with CHF5633 improves lung function and lung architecture, and attenuates inflammation in severe ARDS in adult rabbits similarly to Poractant alfa. Clinical trials have so far not yielded conclusive results, but exogenous surfactant may be a valid supportive treatment for patients with ARDS given its anti-inflammatory and lung-protective effects.

Time-Dependent Oxidative Alterations in Plasma and Lung Tissue after Meconium Aspiration in a Rabbit Model.

Aspirated meconium into a newborn's airways induces the transcription of pro-oxidative mediators that cooperate in the pathogenesis of inflammatory changes and may negatively affect the commonly used exogenous surfactant therapy. However, inflammation is not treated at present, nor is the time dependence of oxidative damage known. The aim of our study was to describe the time course of oxidative stress marker production during meconium aspiration syndrome (MAS) and its relationship to leukocyte infiltration. New Zealand rabbits were instilled with saline or meconium suspension and ventilated for 5.5 h. Respiratory parameters were recorded and blood samples were taken before meconium application and in time intervals of 15 and 30 min, 1.0, 1.5, 3.5 and 5.5 h after application to evaluate oxidative markers and differential leukocytes count. Meconium aspiration led to a worsening of respiratory parameters and a decrease in leukocytes in the first 15 min. Changes in leukocytes were correlated both with nitrotyrosine (3NT) levels and thiobarbituric acid reactive substance (TBARS) levels, with the latter also related to changes in neutrophil count. The production of 3NT and TBARS increased in 1.5 and 3.5 h, respectively, in different ways, suggesting more than one source of oxidative agents and a potential risk of exogenous surfactant inactivation in a short time. We observed that MAS triggered neutrophil migration to the alveolar space and activation, as shown by the increased expression of pro-inflammatory cytokines and generation of indicators of oxidative damage to proteins and lipids during the time period when iNOS and NO metabolites were released.