scholarly journals Activity and biophysical inhibition resistance of a novel synthetic lung surfactant containing Super-Mini-B DATK peptide

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e1528 ◽  
Author(s):  
Robert H. Notter ◽  
Zhengdong Wang ◽  
Frans J. Walther
Keyword(s):  
Fatty Acids ◽  
Surface Tension ◽  
Free Fatty Acids ◽  
Surface Activity ◽  
Dynamic Compression ◽  
Physiological Activity ◽  
Lung Surfactant ◽  
Synthetic Surfactant ◽  
Dynamic Surface ◽  
Surfactant Deficiency

Background/objectives.This study examines the surface activity, resistance to biophysical inhibition, and pulmonary efficacy of a synthetic lung surfactant containing glycerophospholipids combined with Super Mini-B (S-MB) DATK, a novel and stable molecular mimic of lung surfactant protein (SP)-B. The objective of the work is to test whether S-MB DATK synthetic surfactant has favorable biophysical and physiological activity for future use in treating surfactant deficiency or dysfunction in lung disease or injury.Methods.The structure of S-MB DATK peptide was analyzed by homology modeling and by FTIR spectroscopy. Thein vitrosurface activity and inhibition resistance of synthetic S-MB DATK surfactant was assessed in the presence and absence of albumin, lysophosphatidylcholine (lyso-PC), and free fatty acids (palmitoleic and oleic acid). Adsorption and dynamic surface tension lowering were measured with a stirred subphase dish apparatus and a pulsating bubble surfactometer (20 cycles/min, 50% area compression, 37 °C).In vivopulmonary activity of S-MB DATK surfactant was measured in ventilated rabbits with surfactant deficiency/dysfunction induced by repeated lung lavages that resulted in arterial PO2values <100 mmHg.Results.S-MB DATK surfactant had very high surface activity in all assessments. The preparation adsorbed rapidly to surface pressures of 46–48 mN/m at 37 °C (low equilibrium surface tensions of 22–24 mN/m), and reduced surface tension to <1 mN/m under dynamic compression on the pulsating bubble surfactometer. S-MB DATK surfactant showed a significant ability to resist inhibition by serum albumin, C16:0 lyso-PC, and free fatty acids, but surfactant inhibition was mitigated by increasing surfactant concentration. S-MB DATK synthetic surfactant quickly improved arterial oxygenation and lung compliance after intratracheal instillation to ventilated rabbits with severe surfactant deficiency.Conclusions.S-MB DATK is an active mimic of native SP-B. Synthetic surfactants containing S-MB DATK (or related peptides) combined with lipids appear to have significant future potential for treating clinical states of surfactant deficiency or dysfunction, such as neonatal and acute respiratory distress syndromes.

Surface activity of a synthetic lung surfactant containing a phospholipase-resistant phosphonolipid analog of dipalmitoyl phosphatidylcholine

2003 ◽  
Vol 285 (3) ◽  
pp. L550-L559 ◽  
Author(s):  
Z. Wang ◽  
A. L. Schwan ◽  
L. L. Lairson ◽  
J. S. O'Donnell ◽  
G. F. Byrne ◽  
...  
Keyword(s):  
Serum Albumin ◽  
Surface Activity ◽  
Dynamic Compression ◽  
Lung Surfactant ◽  
Dynamic Surface Tension ◽  
Surfactant Proteins ◽  
Chemical Degradation ◽  
Dynamic Surface ◽  
Dipalmitoyl Phosphatidylcholine ◽  
Surfactant Dysfunction

Surface activity and sensitivity to inhibition from phospholipase A2 (PLA2), lysophosphatidylcholine (LPC), and serum albumin were studied for a synthetic C16:0 diether phosphonolipid (DEPN-8) combined with 1.5% by weight of mixed hydrophobic surfactant proteins (SP)-B/C purified from calf lung surfactant extract (CLSE). Pure DEPN-8 had better adsorption and film respreading than the major lung surfactant phospholipid dipalmitoyl phosphatidylcholine and reached minimum surface tensions <1 mN/m under dynamic compression on the Wilhelmy balance and on a pulsating bubble surfactometer (37°C, 20 cycles/min, 50% area compression). DEPN-8 + 1.5% SP-B/C exhibited even greater adsorption and had overall dynamic surface tension lowering equal to CLSE on the bubble. In addition, films of DEPN-8 + 1.5% SP-B/C on the Wilhelmy balance had better respreading than CLSE after seven (but not two) cycles of compression-expansion at 23°C. DEPN-8 is structurally resistant to degradation by PLA2, and DEPN-8 + 1.5% SP-B/C maintained high adsorption and dynamic surface activity in the presence of this enzyme. Incubation of CLSE with PLA2 led to chemical degradation, generation of LPC, and reduced surface activity. DEPN-8 + 1.5% SP-B/C was also more resistant than CLSE to direct biophysical inhibition by LPC, and the two were similar in their sensitivity to biophysical inhibition by serum albumin. These findings indicate that synthetic surfactants containing DEPN-8 combined with surfactant proteins or related synthetic peptides have potential utility for treating surfactant dysfunction in inflammatory lung injury.

Effects of hemoglobin and cell membrane lipids on pulmonary surfactant activity

1987 ◽  
Vol 63 (4) ◽  
pp. 1434-1442 ◽  
Author(s):  
B. A. Holm ◽  
R. H. Notter
Keyword(s):  
Surface Tension ◽  
Erythrocyte Membrane ◽  
Membrane Lipids ◽  
Dynamic Compression ◽  
Lung Surfactant ◽  
Lung Mechanics ◽  
Exogenous Surfactant ◽  
Dynamic Surface ◽  
Surfactant Replacement ◽  
Surfactant Replacement Therapy

These experiments characterize the effects of hemoglobin and erythrocyte membrane lipids on the dynamic surface activity and adsorption facility of whole lung surfactant (LS) and a calf lung surfactant extract (CLSE) used clinically in surfactant replacement therapy for the neonatal respiratory distress syndrome (RDS). The results show that, at concentrations from 25 to 200 mg/ml, hemoglobin (Hb) increased the minimum dynamic surface tension of LS or CLSE mixtures (0.5 and 1.0 mumol/ml) from less than 1 to 25 dyn/cm on an oscillating bubble apparatus at 37 degrees C. Similarly, erythrocyte membrane lipids (0.5–3 mumol/ml) also prevented LS and CLSE suspensions (0.5–2.0 mumol/ml) from lowering surface tension below 19 dyn/cm under dynamic compression on the bubble. Surface pressure-time adsorption isotherms for LS suspensions (0.084 and 0.168 mumol phospholipid/ml) were also adversely affected by Hb (0.3–2.5 mg/ml), having a slower adsorption rate and magnitude. Significantly, these inhibitory effects of Hb and membrane lipids could be abolished if LS and CLSE concentrations were raised to high levels. In complementary physiological experiments, instillation of Hb, membrane lipids, or albumin into excised rat lungs was shown to cause a decrease in pressure-volume compliance. This decreased compliance was most prominent in lungs made partially surfactant deficient before inhibitor delivery and could be reversed by supplementation with active exogenous surfactant. Taken together, these data show that molecular components in hemorrhagic pulmonary edema can biophysically inactivate endogenous LS and adversely affect lung mechanics. Moreover, exogenous surfactant replacement can reverse this process even in the continued presence of inhibitor molecules and thus has potential utility in therapy for adult as well as neonatal RDS.

Inhibition of surfactant activity byPneumocystis cariniiorganisms and components in vitro

2005 ◽  
Vol 288 (6) ◽  
pp. L1124-L1131 ◽  
Author(s):  
Zhengdong Wang ◽  
Adam Foye ◽  
Yusuo Chang ◽  
Patricia R. Chess ◽  
Terry W. Wright ◽  
...  
Keyword(s):  
Surface Tension ◽  
Surface Activity ◽  
Total Phospholipid ◽  
Lung Surfactant ◽  
Pneumocystis Carinii ◽  
Protein A ◽  
Dynamic Surface Tension ◽  
Chemical Components ◽  
Dynamic Surface

This study examines the direct inhibitory effects of Pneumocystis carinii ( Pc) organisms and chemical components on the surface activity and composition of whole calf lung surfactant (WLS) and calf lung surfactant extract (CLSE) in vitro. Incubation of WLS suspensions with intact Pc organisms (107per milligram of surfactant phospholipid) did not significantly alter total phospholipid levels or surfactant protein A content. Incubation with intact Pc organisms also did not impair dynamic surface tension lowering in suspensions of WLS or centrifuged large surfactant aggregates on a bubble surfactometer (37°C, 20 cycles/min, 0.5 and 2.5 mg phospholipid/ml). However, exposure of WLS or CLSE to disrupted (sonicated) Pc organisms led to severe detriments in activity, with minimum surface tensions of 17–19 mN/m vs. <1 mN/m for surfactants alone. Extracted hydrophobic chemical components from Pc (98.8% lipids, 0.1 mM) reduced the surface activity of WLS and CLSE similarly to sonicated Pc organisms, whereas extracted hydrophilic chemical components from Pc (primarily proteins) had only minor effects on surface tension lowering. These results indicate that in addition to surfactant dysfunction induced by inflammatory lung injury and edema-derived inhibitors in Pc pneumonia, disrupted Pc organisms in the alveolar lumen also have the potential to directly inhibit endogenous and exogenous lung surfactants in affected patients.

scholarly journals Synthetic lung surfactants containing SP-B and SP-C peptides plus novel phospholipase-resistant lipids or glycerophospholipids

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2635 ◽  
Author(s):  
Robert H. Notter ◽  
Rohun Gupta ◽  
Adrian L. Schwan ◽  
Zhengdong Wang ◽  
Mohanad Gh Shkoor ◽  
...  
Keyword(s):  
Surface Tension ◽  
Dynamic Compression ◽  
Lung Compliance ◽  
Arterial Oxygenation ◽  
Lung Surfactants ◽  
Dynamic Surface ◽  
Surfactant Deficiency ◽  
Dynamic Lung Compliance ◽  
Synthetic Surfactants

BackgroundThis study examines the biophysical and preclinical pulmonary activity of synthetic lung surfactants containing novel phospholipase-resistant phosphonolipids or synthetic glycerophospholipids combined with Super Mini-B (S-MB) DATK and/or SP-Css ion-lock 1 peptides that replicate the functional biophysics of surfactant proteins (SP)-B and SP-C. Phospholipase-resistant phosphonolipids used in synthetic surfactants are DEPN-8 and PG-1, molecular analogs of dipalmitoyl phosphatidylcholine (DPPC) and palmitoyl-oleoyl phosphatidylglycerol (POPG), while glycerophospholipids used are active lipid components of native surfactant (DPPC:POPC:POPG 5:3:2 by weight). The objective of the work is to test whether these novel lipid/peptide synthetic surfactants have favorable preclinical activity (biophysical, pulmonary) for therapeutic use in reversing surfactant deficiency or dysfunction in lung disease or injury.MethodsSurface activity of synthetic lipid/peptide surfactants was assessedin vitroat 37 °C by measuring adsorption in a stirred subphase apparatus and dynamic surface tension lowering in pulsating and captive bubble surfactometers. Shear viscosity was measured as a function of shear rate on a Wells-Brookfield micro-viscometer.In vivopulmonary activity was determined by measuring lung function (arterial oxygenation, dynamic lung compliance) in ventilated rats and rabbits with surfactant deficiency/dysfunction induced by saline lavage to lower arterial PO2to <100 mmHg, consistent with clinical acute respiratory distress syndrome (ARDS).ResultsSynthetic surfactants containing 5:3:2 DPPC:POPC:POPG or 9:1 DEPN-8:PG-1 combined with 3% (by wt) of S-MB DATK, 3% SP-Css ion-lock 1, or 1.5% each of both peptides all adsorbed rapidly to low equilibrium surface tensions and also reduced surface tension to ≤1 mN/m under dynamic compression at 37 °C. However, dual-peptide surfactants containing 1.5% S-MB DATK + 1.5% SP-Css ion-lock 1 combined with 9:1 DEPN-8:PG-1 or 5:3:2 DPPC:POPC:POPG had the greatestin vivoactivity in improving arterial oxygenation and dynamic lung compliance in ventilated animals with ARDS. Saline dispersions of these dual-peptide synthetic surfactants were also found to have shear viscosities comparable to or below those of current animal-derived surfactant drugs, supporting their potential ease of deliverability by instillation in future clinical applications.DiscussionOur findings support the potential of dual-peptide synthetic lipid/peptide surfactants containing S-MB DATK + SP-Css ion-lock 1 for treating diseases of surfactant deficiency or dysfunction. Moreover, phospholipase-resistant dual-peptide surfactants containing DEPN-8/PG-1 may have particular applications in treating direct forms of ARDS where endogenous phospholipases are present in the lungs.

Content-dependent activity of lung surfactant protein B in mixtures with lipids

2002 ◽  
Vol 283 (5) ◽  
pp. L897-L906 ◽  
Author(s):  
Z. Wang ◽  
J. E. Baatz ◽  
B. A. Holm ◽  
R. H. Notter
Keyword(s):  
Surface Activity ◽  
Physiological Activity ◽  
Lung Surfactant ◽  
Dynamic Surface Tension ◽  
Surfactant Protein ◽  
Surface Tensions ◽  
Dynamic Surface ◽  
Minimum Surface ◽  
Dependent Activity ◽  
Lung Surfactant Protein

The content-dependent activity of surfactant protein (SP)-B was studied in mixtures with dipalmitoyl phosphatidylcholine (DPPC), synthetic lipids (SL), and purified phospholipids (PPL) from calf lung surfactant extract (CLSE). At fixed SP-B content, adsorption and dynamic surface tension lowering were ordered as PPL/SP-B ≈ SL/SP-B > DPPC/SP-B. All mixtures were similar in having increased surface activity as SP-B content was incrementally raised from 0.05 to 0.75% by weight. SP-B had small but measurable effects on interfacial properties even at very low levels ≤0.1% by weight. PPL/SP-B (0.75%) had the highest adsorption and dynamic surface activity, approaching the behavior of CLSE. All mixtures containing 0.75% SP-B reached minimum surface tensions <1 mN/m in pulsating bubble studies at low phospholipid concentration (1 mg/ml). Mixtures of PPL or SL with SP-B (0.5%) also had minimum surface tensions <1 mN/m at 1 mg/ml, whereas DPPC/SP-B (0.5%) reached <1 mN/m at 2.5 mg/ml. Physiological activity also was strongly dependent on SP-B content. The ability of instilled SL/SP-B mixtures to improve surfactant-deficient pressure-volume mechanics in excised lavaged rat lungs increased as SP-B content was raised from 0.1 to 0.75% by weight. This study emphasizes the crucial functional activity of SP-B in lung surfactants. Significant differences in SP-B content between exogenous surfactants used to treat respiratory disease could be associated with substantial activity variations.

Differential sensitivity to fibrinogen inhibition of SP-C- vs. SP-B-based surfactants

1992 ◽  
Vol 262 (3) ◽  
pp. L286-L291 ◽  
Author(s):  
W. Seeger ◽  
A. Gunther ◽  
C. Thede
Keyword(s):  
Surface Tension ◽  
Rank Order ◽  
Dynamic Compression ◽  
Phospholipid Fatty Acid ◽  
Lung Surfactant ◽  
Dynamic Surface Tension ◽  
Inhibitory Effect ◽  
Differential Sensitivity ◽  
Dynamic Surface ◽  
Zero Values

Inhibition of surfactant function by plasma-derived proteins is assumed to occur under conditions of alveolar protein leakage. We investigated surface properties and sensitivity to the inhibitory capacity of fibrinogen (Fbg) of artificial surfactants in a pulsating-bubble surfactometer. Phospholipid-fatty acid mixtures (PLM) with or without hydrophobic apoproteins [natural bovine surfactant proteins (SP) B and C, recombinant human SP-C] were used. Without Fbg, all apoprotein-based surfactants exhibited rapid absorption facilities and reduced surface tension to near zero values under dynamic compression. Fbg caused a dose-dependent reduction of adsorption kinetics and dynamic surface tension-lowering properties of all surfactant preparations, but there was a marked rank order of “Fbg sensitivity”: PLM without apoprotein being the most sensitive and SP-B-based PLM the least. Fbg sensitivity of recombinant SP-C-based PLM could be lowered dose dependently by adding small amounts of SP-B. For further support of a putative role of SP-B in resistance to Fbg inhibition, calf lung surfactant extract was incubated with monoclonal antibody against SP-B. Without Fbg, anti-SP-B had little influence. However, sensitivity to the inhibitory effect of Fbg was markedly and dose dependently increased by anti-SP-B but not by control immunoglobulin. We conclude that SP-B-based surfactant preparations display markedly lower susceptibility to Fbg inhibition than SP-C combinants.

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

1998 ◽  
Vol 84 (1) ◽  
pp. 146-156 ◽  
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.

Mechanisms of peroxynitrite-induced injury to pulmonary surfactants

1993 ◽  
Vol 265 (6) ◽  
pp. L555-L564 ◽  
Author(s):  
I. Y. Haddad ◽  
H. Ischiropoulos ◽  
B. A. Holm ◽  
J. S. Beckman ◽  
J. R. Baker ◽  
...  
Keyword(s):  
Surface Tension ◽  
Dynamic Compression ◽  
Lung Surfactant ◽  
Thiobarbituric Acid ◽  
Surfactant Protein ◽  
Surfactant Proteins ◽  
Minimum Surface ◽  
Surfactant Protein B ◽  
Minimum Surface Tension ◽  
By Products

Activated alveolar macrophages secrete both nitric oxide and superoxide in the alveolar lining fluid which combine rapidly to form peroxynitrite, a potent oxidizing agent capable of damaging lipids and proteins in biological membranes. Peroxynitrite (1 mM) plus 100 microM Fe3+EDTA inhibited calf lung surfactant extract (CLSE) from reaching a minimum surface tension below 10 mN/m on dynamic compression. Peroxynitrite and its by-products reacted with the unsaturated lipid components of CLSE, as evidenced by the appearance of conjugated dienes and thiobarbituric acid products, and damaged all surfactant proteins. A mixture of the hydrophobic proteins [surfactant protein B (SP-B) and surfactant protein C (SP-C)] exposed to peroxynitrite became incapable of lowering phospholipid minimum surface tension on dynamic compression. Exposure of SP-A to peroxynitrite decreased its ability to cause lipid aggregation and to act synergistically with SP-B and SP-C in lowering surface tension of surfactant lipids. Western blot analysis of SP-A exposed to peroxynitrite was consistent with fragmentation and polymerization of the 28- to 36-kDa triplet band, and amino acid analysis revealed the presence of significant levels of 3-nitro-L-tyrosine. We conclude that peroxynitrite and its reactive intermediates inhibit pulmonary surfactant function by lipid peroxidation and damaging surfactant proteins.

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

2019 ◽  
Vol 3 ◽  
pp. 6 ◽  
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 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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