INTRODUCTION In inflammatory respiratory diseases, the imbalance between proteases and endogenous protease inhibitors leads to an exacerbated activity of human neutrophil elastase (a protease that destroys the extracellular matrix and stimulates proinflammatory cytokine release). Elastase is considered a target in the search for therapeutic treatments for inflammatory respiratory diseases. Pulmonary surfactant is a promising product for this purpose, because in addition to its biophysical function, it has anti-inflammatory properties.
OBJECTIVES Evaluate effect of the Cuban porcine pulmonary surfactant (Surfacen), the rCmPI-II elastase inhibitor, and the Surfacen/rCmPI-II combination on activated neutrophil elastase activity in vitro, and determine if Surfacen’s interface property changes in the presence of the inhibitor.
METHODS The anti-elastase effect of Surfacen, rCmPI-II and the Surfacen/rCmPI-II combination was evaluated in an in vitro model of activated neutrophils, previously purified from the blood of healthy subjects. The cells were stimulated with LPS/fMLP and were incubated with different concentrations of Surfacen, rCmPI-II and the Surfacen/rCmPI-II combination. Elastase activity was measured. The interface property was determined on a Langmuir surface balance.
The new index, called the abdominal adipose deposit index, was obtained by multiplying the subcutaneous fat thickness by visceral fat thickness, both measured by ultrasound. A cutoff point was established that facilitated discernment of an unhealthy phenotype: normal weight but metabolically obese, a cardiometabolic risk factor.
RESULTS Surfacen at 10 mg/mL inhibited 71% of stimulated neutrophil elastase activity. rCmPI-II at 0.1 μM reduced 20% of elastase activity; at 200 μM—the maximum concentration evaluated—inhibition was 68%. Both products had a dose-dependent effect. The Surfacen/inhibitor combination (0.5 mg/mL/80 µM) did not affect the surfactant interface property or the inhibitory activity of rCmPI-II against human neutrophil elastase.
CONCLUSIONS Surfacen and the rCmPI-II inhibitor have an anti-elastase effect on an activated neutrophil model. rCmPI-II does not affect Surfacen’s interface property and, therefore, both can be evaluated for combined use in treating inflammatory lung diseases.
KEYWORDS Pulmonary surfactants, elastase inhibitor, drug carriers, neutrophils, Cuba
INTRODUCTION Acute respiratory distress syndrome is a complex heterogeneous disorder with low incidence but high case fatality in children. Treatment with pulmonary surfactants is a possible option. Surfacen, a Cuban exogenous pulmonary surfactant, has been proven safe and effective in premature newborns with hyaline membrane disease, but evidence regarding its efficacy in older children is still inconclusive.
OBJECTIVE Determine Surfacen’s efficacy in improving oxygenation and increasing survival in children with acute respiratory distress syndrome.
METHODS A multicenter (five pediatric intensive care units in four provinces), open-label, controlled, randomized phase III clinical trial with two treatment groups was conducted from November 2009 through August 2013, with 19 girls and 23 boys aged 1 month to 18 years. The experimental group (20 patients) received conventional treatment (oxygenation and mechanical ventilation) plus intratracheal instillation of Surfacen (100 mg/4 mL) every eight hours for three days. The control group (22 patients) received only conventional treatment. The primary dependent outcome was patient vital status (alive or deceased) 28 days after study enrollment. Other variables and outcomes analyzed were age, sex, ARDS presentation, Kirby index (arterial oxygen tension over inspired oxygen fraction), oxygenation index, static lung compliance, transcutaneous oxygen saturation, radiographic course, mechanical ventilation time and length of stay in neonatal intensive care. Statistical tests used were the chi-square test and Fisher exact test.
RESULTS On day 28, there was 80% survival in the experimental group versus 38.1% in the control group. There were significant differences between the experimental and the control group in Kirby index, oxygenation index, static lung compliance and radiographic course, all favoring the experimental group. For every 2.38 patients treated in total, there was one additional survivor in the experimental group.
CONCLUSIONS When combined with conventional therapy in the regimen employed, Surfacen improves oxygenation and increases survival in children with ARDS.
KEYWORDS Exogenous pulmonary surfactant, acute pulmonary distress syndrome, ARDS, children, intensive care, Cuba
