Surfactant Protein-D Inhibits Lung Inflammation Caused by Ventilation in Premature Newborn Lambs

Abstract

Rationale: Premature newborns frequently require manual ventilation for resuscitation during which lung injury occurs. Although surfactant protein (SP)-D regulates pulmonary inflammation, SP-D levels are low in the preterm lung. Commercial surfactants for treatment of respiratory distress syndrome do not contain SP-D. Objectives: To determine whether addition of recombinant human SP-D (rhSP-D) to commercial surfactant influences lung inflammation in ventilated premature newborn lambs. Methods: Prematurely delivered lambs (130 d gestation age) were resuscitated with 100% O 2 and peak inspiratory pressure 40 cm H 2 O for 20 minutes and then treated with Survanta or Survanta containing rhSP-D. Ventilation was then changed to regulate tidal volume at 8 to 9 ml/kg. At 5 hours of age lambs were killed for sample collection. Measurements and Main Results: Sequential blood gas and tidal volume were similar in lambs treated with or without rhSP-D, indicating that lung immaturity and ventilatory stress used to support premature lambs were comparable between the two groups. Ventilation caused pulmonary inflammation in lambs treated with surfactant alone. In contrast, surfactant containing rhSP-D decreased neutrophil numbers in bronchoalveolar lavage fluid and decreased neutrophil elastase activity in lung tissue. IL-8 mRNA and IL-8 protein were significantly decreased in the 1rhSP-D group lamb lungs, to 20% of those in controls. The addition of rhSP-D also rendered Survanta more resistant to plasma protein inhibition of surfactant function. Conclusions: Treatment with rhSP-D-containing surfactant inhibited lung inflammation and enhanced the resistance of surfactant to inhibition, supporting its potential usefulness for prevention of lung injury in the preterm newborn.

Differential modulation of surfactant protein D under acute and persistent hypoxia in acute lung injury

“…These data were compatible with not only the kinetic analysis of SP-D expression in the in vivo BLM-induced lung injury/fibrosis model but also the differential effect of acute and persistent cellular hypoxia on SP-D expression in alveolar epithelial cells in vitro. Taken together with recent findings showing that local administration of recombinant SP-D might be effective for lung inflammation early in the course of an in vivo model of ALI (1,15,29), persistent hypoxia-induced SP-D repression might be a new therapeutic target in fibrosing alveolitis and lung fibrosis. Further investigation is warranted.…”

Leptin does not influence surfactant synthesis in fetal sheep and mice lungs

“…Three and a half days after injection, preterm lambs were delivered by cesarean section and tracheostomized (24,38). To induce surfactant secretion at birth and evaluate lung function, preterm newborn lambs were ventilated for 30 min with 100% O 2, 4-cmH2O positive endexpiratory pressure (PEEP), and 40/min respiratory rate, and tidal volume (VT) was regulated at 6 ml/kg by changing peak inspiratory pressure (PIP) with maximum PIP set at 38 cmH2O, using pressurelimited infant ventilator (Sechrist Industries, Anaheim, CA).…”

“…VT was monitored (BiCore Monitoring Systems, Anaheim, CA) continuously. A modified ventilation index (MVI) was calculated as (PIP ϫ PCO 2 ϫ respiratory rate) Ϭ 1,000 (38). Umbilical cord catheter was inserted into the aorta for blood gas, blood pressure, and heart rate recordings and 10% dextrose infusion.…”

Untapped Therapeutic Potential of Surfactant Proteins: Is There a Case for Recombinant SP-D Supplementation in Neonatal Lung Disease?

“…The improvement in the abnormal lung phenotype of SP-D-deficient mice after exogenous treatment with recombinant truncated SP-D strongly indicates that recombinant SP-D treatment in SP-D-deficient preterm infants might be beneficial and reduce the risk of developing CLD. A recent paper highlighted the efficacy of a mixture of a recombinant SP-D with Survanta in decreasing inflammation in ventilated preterm lambs compared to Survanta alone [67] . Overall this suggests that there is currently untapped therapeutic potential for the use of recombinant forms of SP-D as supplements to current surfactant formulations for the treatment of neonatal RDS which merit clinical investigation.…”