Synthetic surfactant containing SP-B and SP-C mimics is superior to single-peptide formulations in rabbits with chemical acute lung injury

Abstract

Background. Chemical spills are on the rise and inhalation of toxic chemicals may induce chemical acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Although the pathophysiology of ALI/ARDS is well understood, the absence of specific antidotes has limited the effectiveness of therapeutic interventions.Objectives. Surfactant inactivation and formation of free radicals are important pathways in (chemical) ALI. We tested the potential of lipid mixtures with advanced surfactant protein B and C (SP-B and C) mimics to improve oxygenation and lung compliance in rabbits with lavage- and chemical-induced ALI/ARDS.Methods. Ventilated young adult rabbits underwent repeated saline lung lavages or underwent intratracheal instillation of hydrochloric acid to induce ALI/ARDS. After establishment of respiratory failure rabbits were treated with a single intratracheal dose of 100 mg/kg of synthetic surfactant composed of 3% Super Mini-B (S-MB), a SP-B mimic, and/or SP-C33 UCLA, a SP-C mimic, in a lipid mixture (DPPC:POPC:POPG 5:3:2 by weight), the clinical surfactant Infasurf®, a bovine lung lavage extract with SP-B and C, or synthetic lipids alone. End-points consisted of arterial oxygenation, dynamic lung compliance, and protein and lipid content in bronchoalveolar lavage fluid. Potential mechanism of surfactant action for S-MB and SP-C33 UCLA were investigated with captive bubble surfactometry (CBS) assays.Results. All three surfactant peptide/lipid mixtures and Infasurf equally lowered the minimum surface tension on CBS, and also improved oxygenation and lung compliance. In both animal models, the two-peptide synthetic surfactant with S-MB and SP-C33 UCLA led to better arterial oxygenation and lung compliance than single peptide synthetic surfactants and Infasurf. Synthetic surfactants and Infasurf improved lung function further in lavage- than in chemical-induced respiratory failure, with the difference probably due to greater capillary-alveolar protein leakage and surfactant dysfunction after HCl instillation than following lung lavage. At the end of the duration of the experiments, synthetic surfactants provided more clinical stability in ALI/ARDS than Infasurf, and the protein content of bronchoalveolar lavage fluid was lowest for the two-peptide synthetic surfactant with S-MB and SP-C33 UCLA.Conclusion. Advanced synthetic surfactant with robust SP-B and SP-C mimics is better equipped to tackle surfactant inactivation in chemical ALI than synthetic surfactant with only a single surfactant peptide or animal-derived surfactant.

Synthetic lung surfactant reduces alveolar-capillary protein leakage in surfactant-deficient rabbits

“…SP-B and SP-C peptides were synthesized on a Symphony Multiple Peptide Synthesizer (Protein Technologies, Tucson, AZ) with standard Fmoc chemistry, purified by reverse phase HPLC, and had their molecular weights verified by MALDI-TOF [12–19]. Synthetic surfactant preparations were formulated by mixing DPPC:POPC:POPG at a 5:3:2 weight ratio [20] with 3% of native SP-B or the SP-B peptides MB [12] or SMB [13] or an inactive SP-B “mutant” thereof; 3% of the SP-C peptides SP-Cff [14, 15], SP-C33 [16, 17], or SP-Css ion–lock 1 [15], or an inactive “mutant” thereof; 1.5% each of a representative of the SP-B and SP-C peptide groups (MB + SP-C33, SMB + SP-C33, SP-Cff, or SP-Css ion-lock 1); or surfactant lipids alone.…”

“…Anesthesia, surgery, lavage, ventilation, and monitoring used in this study are the same as previously described [15, 18, 19]. Briefly, young adult New Zealand white rabbits (weight 1.0–1.3 kg) received anesthesia via a percutaneous intravenous line, were intubated and ventilated, and had a carotid arterial line inserted.…”

Synthetic surfactants with SP‐B and SP‐C analogues to enable worldwide treatment of neonatal respiratory distress syndrome and other lung diseases

“…Since apparently both SP‐B and SP‐C need to be present in natural‐derived surfactant preparations for optimal activity in an animal model of neonatal RDS , it is reasonable to assume that also synthetic surfactants need representatives of both SP‐B and SP‐C. This is supported by experimental data; synthetic surfactants that contain SP‐C33 plus either Mini‐B , Mini‐BLeu or Super Mini‐B are superior in animal models of RDS or ARDS to surfactants that contain only one of the proteins. Most respiratory parameters are improved by the combination of SP‐B and SP‐C analogues; however, in particular, the lung gas volumes at the end of expiration in animals ventilated without PEEP seem to be a sensitive measure of the presence of both SP‐B‐ and SP‐C‐like properties .…”

Recent Developments in mRNA-Based Protein Supplementation Therapy to Target Lung Diseases

“…Accompanied by physical measures, corticosteroids, or immunosuppressants and repeated lung lavage, surfactant replacements have shown improvement in the disease condition until lung transplantation. [139][140][141][142][143][144] The potential risks with animal-derived protein include immunological reactions and transmission of animal-derived diseases, justifying the need for standardized human-like alternatives. [145][146][147] One alternative involves synthetic mimics that have shown superior surfactant properties.…”