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

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.

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

Gates Open Research ◽

10.12688/gatesopenres.12899.1 ◽

2019 ◽

Vol 3 ◽

pp. 6 ◽

Cited By ~ 1

Author(s):

Frans J. Walther ◽

Monik Gupta ◽

Michael M. Lipp ◽

Holly Chan ◽

John Krzewick ◽

...

Keyword(s):

Lung Function ◽

Surface Activity ◽

Lung Surfactant ◽

Respiratory Support ◽

Low Flow ◽

Synthetic Surfactant ◽

Aerosol Delivery ◽

Dry Powder ◽

Non Invasive

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 active 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.

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Species pattern of phosphatidylinositol from lung surfactant and a comparison of the species pattern of phosphatidylinositol and phosphatidylglycerol synthesized de novo in lung microsomal fractions

Biochemical Journal ◽

10.1042/bj2540067 ◽

1988 ◽

Vol 254 (1) ◽

pp. 67-71 ◽

Cited By ~ 9

Author(s):

B Rüstow ◽

Y Nakagawa ◽

H Rabe ◽

K Waku ◽

D Kunze

Keyword(s):

Lung Function ◽

Molecular Species ◽

De Novo ◽

Lung Surfactant ◽

Minor Component ◽

Main Species ◽

Surfactant Phospholipids ◽

Species Pattern ◽

A Minor

1. Phosphatidylinositol (PI) is a minor component of lung surfactant which may be able to replace the functionally important phosphatidylglycerol (PG) [Beppu, Clements & Goerke (1983) J. Appl. Physiol. 55, 496-502] without disturbing lung function. The dipalmitoyl species is one of the main species for both PI (14.4%) and PG (16.9%). Besides the C16:0--C16:0 species, the C16:0--C18:0, C16:0--C18:1, C16:0--C18:2 and C18:0--C18:1 species showed comparable proportions in the PG and PI fractions. These similarities of the species patterns and the acidic character of both phospholipids could explain why surfactant PG may be replaced by PI. 2. PI and PG were radiolabelled by incubation of microsomal fractions with [14C]glycerol 3-phosphate (Gro3P). For 11 out of 14 molecular species of PI and PG we measured comparable proportions of radioactivity. The radioactivity of these 11 species accounted together for more than 80% of the total. The addition of inositol to the incubation system decreased the incorporation in vitro of Gro3P into PG and CDP-DG (diacylglycerol) of lung microsomes (microsomal fractions), but did not change the distribution of radioactivity among the molecular species of PG. These results supported the idea that both acidic surfactant phospholipids may be synthesized de novo from a common CDP-DG pool in lung microsomes.

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Alterations in the surface properties of lung surfactant in the torpid marsupial Sminthopsis crassicaudata

Journal of Applied Physiology ◽

10.1152/jappl.1998.84.1.146 ◽

1998 ◽

Vol 84 (1) ◽

pp. 146-156 ◽

Cited By ~ 21

Author(s):

Olga V. Lopatko ◽

Sandra Orgeig ◽

Christopher B. Daniels ◽

David Palmer

Keyword(s):

Surface Tension ◽

Surface Properties ◽

Surface Activity ◽

Pulmonary Surfactant ◽

Lung Surfactant ◽

Lung Compliance ◽

Equilibrium Surface Tension ◽

Sminthopsis Crassicaudata

Lopatko, Olga V., Sandra Orgeig, Christopher B. Daniels, and David Palmer. Alterations in the surface properties of lung surfactant in the torpid marsupial Sminthopsis crassicaudata. J. Appl. Physiol. 84(1): 146–156, 1998.—Torpor changes the composition of pulmonary surfactant (PS) in the dunnart Sminthopsis crassicaudata [C. Langman, S. Orgeig, and C. B. Daniels. Am. J. Physiol. 271 ( Regulatory Integrative Comp. Physiol. 40): R437–R445, 1996]. Here we investigated the surface activity of PS in vitro. Five micrograms of phospholipid per centimeter squared surface area of whole lavage (from mice or from warm-active, 4-, or 8-h torpid dunnarts) were applied dropwise onto the subphase of a Wilhelmy-Langmuir balance at 20°C and stabilized for 20 min. After 4 h of torpor, the adsorption rate increased, and equilibrium surface tension (STeq), minimal surface tension (STmin), and the %area compression required to achieve STmin decreased, compared with the warm-active group. After 8 h of torpor, STmin decreased [from 5.2 ± 0.3 to 4.1 ± 0.3 (SE) mN/m]; %area compression required to achieve STmindecreased (from 43.4 ± 1.0 to 27.4 ± 0.8); the rate of adsorption decreased; and STeqincreased (from 26.3 ± 0.5 to 38.6 ± 1.3 mN/m). ST-area isotherms of warm-active dunnarts and mice at 20°C had a shoulder on compression and a plateau on expansion. These disappeared on the isotherms of torpid dunnarts. Samples of whole lavage (from warm-active and 8-h torpor groups) containing 100 μg phospholipid/ml were studied by using a captive-bubble surfactometer at 37°C. After 8 h of torpor, STmin increased (from 6.4 ± 0.3 to 9.1 ± 0.3 mN/m) and %area compression decreased in the 2nd (from 88.6 ± 1.7 to 82.1 ± 2.0) and 3rd (from 89.1 ± 0.8 to 84.9 ± 1.8) compression-expansion cycles, compared with warm-active dunnarts. ST-area isotherms of warm-active dunnarts at 37°C did not have a shoulder on compression. This shoulder appeared on the isotherms of torpid dunnarts. In conclusion, there is a strong correlation between in vitro changes in surface activity and in vivo changes in lipid composition of PS during torpor, although static lung compliance remained unchanged (see Langman et al. cited above). Surfactant from torpid animals is more active at 20°C and less active at 37°C than that of warm-active animals, which may represent a respiratory adaptation to low body temperatures of torpid dunnarts.

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Interaction of transferrin saturated with iron with lung surfactant in respiratory failure

Journal of Applied Physiology ◽

10.1152/jappl.1994.77.2.757 ◽

1994 ◽

Vol 77 (2) ◽

pp. 757-766 ◽

Cited By ~ 16

Author(s):

M. Hallman ◽

A. Sarnesto ◽

K. Bry

Keyword(s):

Respiratory Failure ◽

Surface Activity ◽

Lung Surfactant ◽

Protein A ◽

Surfactant Protein ◽

Lung Damage ◽

Epithelial Lining ◽

Surface Absorption ◽

Epithelial Lining Fluid

Proteins that decrease the surface activity of surfactant accumulate in epithelial lining fluid in respiratory failure. The aim of this study was to isolate a surfactant inhibitor from the airways of rabbits in acute respiratory failure induced by bronchoalveolar lavage (BAL). This inhibitor was identified as being transferrin (TF). Unlike serum TF, TF recovered in respiratory failure was saturated with iron (Fe(3+)-TF). Fe(3+)-TF decreased the surface activity of normal surfactant in vitro, whereas iron-free TF had no effect. In the presence of H2O2 and a reducing agent, Fe(+3)-TF inactivated the surfactant complex: the surface absorption rate was decreased, immunoreactive surfactant protein A was decreased, and malondialdehyde was formed. The acute effects of Fe(3+)-TF and iron-free TF applied to the airways were studied in animal models. In respiratory failure induced by BAL, Fe(3+)-TF deteriorated respiratory failure, whereas iron-free TF had no effect. In respiratory failure induced by hyperoxia for 48 h, administration of iron-free TF ameliorated the respiratory failure and improved the surface activity in BAL. We propose that Fe(3+)-TF accumulating in epithelial lining fluid during lung damage contributes to surfactant inhibition and promotes the formation of free radicals that inactivate the surfactant system.

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Lipid composition greatly affects the in vitro surface activity of lung surfactant protein mimics

Colloids and Surfaces B Biointerfaces ◽

10.1016/j.colsurfb.2007.01.001 ◽

2007 ◽

Vol 57 (1) ◽

pp. 37-55 ◽

Cited By ~ 16

Author(s):

Shannon L. Seurynck-Servoss ◽

Nathan J. Brown ◽

Michelle T. Dohm ◽

Cindy W. Wu ◽

Annelise E. Barron

Keyword(s):

Surface Activity ◽

Lipid Composition ◽

Lung Surfactant ◽

Surfactant Protein ◽

Protein Mimics ◽

Lung Surfactant Protein

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High-Performing Dry Powder Inhalers of Paclitaxel DPPC/DPPG Lung Surfactant-Mimic Multifunctional Particles in Lung Cancer: Physicochemical Characterization, In Vitro Aerosol Dispersion, and Cellular Studies

AAPS PharmSciTech ◽

10.1208/s12249-014-0182-z ◽

2014 ◽

Vol 15 (6) ◽

pp. 1574-1587 ◽

Cited By ~ 24

Author(s):

Samantha A. Meenach ◽

Kimberly W. Anderson ◽

J. Zach Hilt ◽

Ronald C. McGarry ◽

Heidi M. Mansour

Keyword(s):

Lung Cancer ◽

Lung Surfactant ◽

Physicochemical Characterization ◽

Dry Powder Inhalers ◽

Dry Powder ◽

High Performing ◽

Aerosol Dispersion

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Chitosan Enhances the In Vitro Surface Activity of Dilute Lung Surfactant Preparations and Resists Albumin-Induced Inactivation

Pediatric Research ◽

10.1203/01.pdr.0000227558.14024.57 ◽

2006 ◽

Vol 60 (2) ◽

pp. 125-130 ◽

Cited By ~ 41

Author(s):

Yi Y Zuo ◽

Hamdi Alolabi ◽

Arash Shafiei ◽

Ningxi Kang ◽

Zdenka Policova ◽

...

Keyword(s):

Surface Activity ◽

Lung Surfactant

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High Flow Nasal Cannula Oxygenation

JMS SKIMS ◽

10.33883/jms.v23i3.784 ◽

2020 ◽

Vol 23 (3) ◽

Author(s):

Tajamul Hussain Shah ◽

Suhail Mantoo ◽

Rafi Ahmad Jan

Keyword(s):

Face Mask ◽

High Flow ◽

Nasal Cannula ◽

Respiratory Support ◽

Low Flow ◽

Invasive Ventilation ◽

High Flow Nasal Cannula ◽

Non Invasive ◽

Non Invasive Ventilation ◽

Flow Devices

High Flow Nasal Cannula Oxygenation The current pandemic of COVID-19 caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tested the healthcare infrastructure throughout the globe at all possible levels. Early reports suggest about 20% of patients infected with SARS-CoV-2 require hospitalization and 5-8% require admission to intensive care unit (ICU) due to severe disease.Supplementation of oxygen provided by various conventional oxygen therapy (COT) devices (like nasal prongs, face mask, venture mask or non-rebreather mask) may not be sufficient in cases of worsening respiratory failure. One form of escalating respiratory support in such patients is a high flow nasal oxygenation device. High flow nasal cannula oxygenation (HFNC) is a form of non invasive respiratory support. It acts as a bridge between low flow devices and non invasive ventilation and may reduce the need for intubation.

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A sulfur-free peptide mimic of surfactant protein B (B-YL) exhibits high in vitro and in vivo surface activities

Gates Open Research ◽

10.12688/gatesopenres.12799.2 ◽

2018 ◽

Vol 2 ◽

pp. 13 ◽

Cited By ~ 2

Author(s):

Frans J. Walther ◽

Monik Gupta ◽

Larry M. Gordon ◽

Alan J. Waring

Keyword(s):

Ftir Spectroscopy ◽

Preterm Infants ◽

Surface Activity ◽

High Surface ◽

Lung Surfactant ◽

Scale Up ◽

Free Oxygen Radical ◽

Α Helix

Background: Animal-derived surfactants containing surfactant proteins B (SP-B) and C (SP-C) are used to treat respiratory distress syndrome (RDS) in preterm infants. SP-B (79 residues) plays a pivotal role in lung function and the design of synthetic lung surfactant. Super Mini-B (SMB), a 41-residue peptide based on the N- and C-domains of SP-B covalently joined with a turn and two disulfides, folds as an α-helix hairpin mimicking the properties of these domains in SP-B. Here, we studied ‘B-YL’, a 41-residue SMB variant that has its four cysteine and two methionine residues replaced by tyrosine and leucine, respectively, to test whether these hydrophobic substitutions produce a surface-active, α-helix hairpin. Methods: Structure and function of B-YL and SMB in surfactant lipids were compared with CD and FTIR spectroscopy, and surface activity with captive bubble surfactometry and in lavaged, surfactant-deficient adult rabbits. Results: CD and FTIR spectroscopy of B-YL in surfactant lipids showed secondary structures compatible with peptide folding as an α-helix hairpin, similar to SMB in lipids. B-YL in surfactant lipids demonstrated excellent in vitro surface activity and good oxygenation and dynamic compliance in lavaged, surfactant-deficient adult rabbits, suggesting that the four tyrosine substitutions are an effective replacement for the disulfide-reinforced helix-turn of SMB. Here, the B-YL fold may be stabilized by a core of clustered tyrosines linking the N- and C-helices through non-covalent interactions involving aromatic rings. Conclusions: ‘Sulfur-free’ B-YL forms an amphipathic helix-hairpin in surfactant liposomes with high surface activity and is functionally similar to SMB and native SP-B. The removal of the cysteines makes B-YL more feasible to scale up production for clinical application. B-YL’s possible resistance against free oxygen radical damage to methionines by substitutions with leucine provides an extra edge over SMB in the treatment of respiratory failure in preterm infants with RDS.

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