Aerosol delivery of dry powder synthetic lung surfactant to surfactant-deficient rabbits and preterm lambs on non-invasive respiratory support.

Frans J Walther,Michael M Lipp,Larry M Gordon,Monik Gupta,Alan J Waring,John Krzewick,Holly Chan

doi:10.12688/gatesopenres.12899.2

Abstract

Background: The development of synthetic lung surfactant for preterm infants has focused on peptide analogues of native surfactant proteins B and C (SP-B and SP-C). Non-invasive respiratory support with nasal continuous positive airway pressure (nCPAP) may benefit from synthetic surfactant for aerosol delivery. Methods: A total of three dry powder (DP) surfactants, consisting of phospholipids and the SP-B analogue Super Mini-B (SMB), and one negative control DP surfactant without SMB, were produced with the Acorda Therapeutics ARCUS® Pulmonary Dry Powder Technology. Structure of the DP surfactants was compared with FTIR spectroscopy, in vitro surface activity with captive bubble surfactometry, and in vivo activity in surfactant-deficient adult rabbits and preterm lambs. In the animal experiments, intratracheal (IT) aerosol delivery was compared with surfactant aerosolization during nCPAP support. Surfactant dosage was 100 mg/kg of lipids and aerosolization was performed using a low flow inhaler. Results: FTIR spectra of the three DP surfactants each showed secondary structures compatible with peptide folding as an α-helix hairpin, similar to that previously noted for surface-active SMB in other lipids. The DP surfactants with SMB demonstrated in vitro surface activity <1 mN/m. Oxygenation and lung function increased quickly after IT aerosolization of DP surfactant in both surfactant-deficient rabbits and preterm lambs, similar to improvements seen with clinical surfactant. The response to nCPAP aerosol delivery of DP surfactant was about 50% of IT aerosol delivery, but could be boosted with a second dose in the preterm lambs. Conclusions: Aerosol delivery of DP synthetic surfactant during non-invasive respiratory support with nCPAP significantly improved oxygenation and lung function in surfactant-deficient animals and this response could be enhanced by giving a second dose. Aerosol delivery of DP synthetic lung surfactant has potential for clinical applications.

Highlights

Lung surfactant is a lipid-protein mixture that is synthesized by alveolar type II cells and secreted into the alveoli to reduce surface tension at the air-liquid interface
The realization that the etiology of chronic lung injury (a.k.a. bronchopulmonary dysplasia, BPD) is multifactorial and intubation and mechanical ventilation are associated with a higher risk of BPD has led to a preference for non-invasive respiratory support with nasal continuous positive airway pressure in preterm infants3
We report the development of surface-active dry powder (DP) synthetic lung surfactant formulations, their in vitro surface activity in the captive bubble surfactometer and their in vivo surface activity following aerosol delivery in spontaneously breathing, surfactant-deficient rabbits and preterm lambs supported with nasal continuous positive airway pressure (nCPAP)

Summary

Introduction

Lung surfactant is a lipid-protein mixture that is synthesized by alveolar type II cells and secreted into the alveoli to reduce surface tension at the air-liquid interface. Animal surfactant has some major drawbacks, such as limited supplies, complex production and sterilization processes, high production costs, and the need for intratracheal (IT) delivery. This has stimulated the design and testing of synthetic lung surfactant formulations with peptide mimics of the pivotal surfactant protein B (SP-B) and the less essential surfactant protein C (SP-C). Response: We redid figure 2, thereby superimposing the graphs on one another and changing the legend

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Conclusion