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.

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.

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.

Neonatal calves develop airflow limitation due to chronic hypobaric hypoxia

1991 ◽  
Vol 70 (1) ◽  
pp. 384-390 ◽  
Author(s):  
S. C. Inscore ◽  
K. R. Stenmark ◽  
C. Orton ◽  
C. G. Irvin
Keyword(s):  
Pulmonary Hypertension ◽  
Hypobaric Hypoxia ◽  
Fibrous Tissue ◽  
Lung Compliance ◽  
Airflow Limitation ◽  
Mean Pulmonary Arterial Pressure ◽  
Neonatal Calves ◽  
Dynamic Lung Compliance

Neonates and infants presenting with pulmonary hypertension and chronic hypoxia often exhibit airway obstruction. To investigate this association, we utilized a system in which neonatal calves are exposed to chronic hypobaric hypoxia and develop severe pulmonary hypertension. For the present study, one of each pair of six age-matched pairs of neonatal calves was continuously exposed to hypobaric hypoxia at 4,500 m (CH); the other remained at 1,500 m. At 2 wk of age, mean pulmonary arterial pressure (MPAP), dynamic lung compliance (Cdyn), resistance (RL), and static respiratory system compliance (Crs) were measured at 4,500 m in both CH and control calves exposed acutely to hypoxia (C). These measurements were repeated after cumulative administrations of nebulized methacholine (MCh). Tissues were removed for histological examination and assessment of bronchial ring contractility to MCh and KCl. After 2 wk of hypobaric hypoxia, MPAP (C 35 +/- 1.7 vs. CH 120 +/- 7 mmHg, P less than 0.001) and RL (C 2.64 +/- 0.16 vs CH 4.99 +/- 0.47 cmH2O.l-1s, P less than 0.001) increased. Cdyn (C 0.100 +/- 0.01 vs. CH 0.082 +/- 0.007 l/cmH2O) and Crs (CH 0.46 +/- 0.003 vs. C 0.59 +/- 0.009 l/cmH2O) were not significantly different. Compared with airways of C calves, airways of CH animals did not exhibit in vivo or in vitro MCh hyperresponsiveness; however, in vitro contractility to KCl of airways from CH animals was significantly increased. Histologically, airways from the CH calves showed increases in airway fibrous tissue and smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory mechanics of a small carnivore: the ferret

1982 ◽  
Vol 52 (4) ◽  
pp. 832-837 ◽  
Author(s):  
A. Vinegar ◽  
E. E. Sinnett ◽  
P. C. Kosch
Keyword(s):  
Total Lung Capacity ◽  
Lung Compliance ◽  
Pulmonary Resistance ◽  
Mustela Putorius ◽  
Tidal Breathing ◽  
Lung Capacity ◽  
Maximum Expiratory Flow ◽  
Residual Capacity ◽  
Dynamic Lung Compliance

The ferret, Mustela putorius furo, is a small relatively inexpensive carnivore with minimal housing requirements. Measurements were made from anesthetized tracheotomized supine males. Values obtained during tidal breathing for six animals (576 +/- 12 g) were as follows: tidal volume, 6.06 +/- 0.30 ml; respiratory frequency, 26.7 +/- 3.9 breaths min-1; dynamic lung compliance, 2.48 +/- 0.21 ml cmH2O-1; pulmonary resistance, 22.56 +/- 1.61 cmH2O . l–1 . s. Pressure-volume curves from nine ferrets revealed almost infinitely compliant chest walls so that lung and total respiratory system curves were essentially the same. Total lung capacity (TLC, 89 +/- 5 ml) and functional residual capacity (17.8 +/- 2.0 ml) were determined by gas freeing the lungs in vivo. The TLC of these ferrets is about the same as in 2.5-kg rabbits. Maximum expiratory flow-volume curves showed peak flows of 10.1 vital capacities (VC) . s-1 at 75% VC and flows of 8.4 and 5.4 VC . s-1 at 50 and 25% VC.

scholarly journals Surfactant dysfunction during overexpression of TGF-β1 precedes profibrotic lung remodeling in vivo

2016 ◽  
Vol 310 (11) ◽  
pp. L1260-L1271 ◽  
Author(s):  
Elena Lopez-Rodriguez ◽  
Caroline Boden ◽  
Mercedes Echaide ◽  
Jesus Perez-Gil ◽  
Martin Kolb ◽  
...  
Keyword(s):  
Surface Tension ◽  
Gene Transfer ◽  
High Surface ◽  
Lung Compliance ◽  
Collagen Fibrils ◽  
Surfactant Proteins ◽  
Septal Wall ◽  
High Surface Tension ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1) is involved in regulation of cellular proliferation, differentiation, and fibrogenesis, inducing myofibroblast migration and increasing extracellular matrix synthesis. Here, TGF-β1 effects on pulmonary structure and function were analyzed. Adenovirus-mediated gene transfer of TGF-β1 in mice lungs was performed and evaluated by design-based stereology, invasive pulmonary function testing, and detailed analyses of the surfactant system 1 and 2 wk after gene transfer. After 1 wk decreased static compliance was linked with a dramatic alveolar derecruitment without edema formation or increase in the volume of septal wall tissue or collagen fibrils. Abnormally high surface tension correlated with downregulation of surfactant proteins B and C. TTF-1 expression was reduced, and, using PLA (proximity ligand assay) technology, we found Smad3 and TTF-1 forming complexes in vivo, which are normally translocated into the nucleus of the alveolar epithelial type II cells (AE2C) but in the presence of TGF-β1 remain in the cytoplasm. AE2C show altered morphology, resulting in loss of total apical surface area per lung and polarity. These changes of AE2C were progressive 2 wk after gene transfer and correlated with lung compliance. Although static lung compliance remained low, the volume of septal wall tissue and collagen fibrils increased 2 wk after gene transfer. In this animal model, the primary effect of TGF-β1 signaling in the lung is downregulation of surfactant proteins, high surface tension, alveolar derecruitment, and mechanical stress, which precede fibrotic tissue remodeling and progressive loss of AE2C polarity. Initial TTF-1 dysfunction is potentially linked to downregulation of surfactant proteins.

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.

scholarly journals Prevention of endogenous leukotriene production during anaphylaxis in the guinea pig by an inhibitor of leukotriene biosynthesis (MK-886) but not by dexamethasone.

1989 ◽  
Vol 170 (6) ◽  
pp. 1905-1918 ◽  
Author(s):  
A Guhlmann ◽  
A Keppler ◽  
S Kästner ◽  
H Krieter ◽  
U B Brückner ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Receptor Antagonist ◽  
Guinea Pigs ◽  
Anaphylactic Shock ◽  
Histamine Receptor ◽  
Inhibitory Effect ◽  
Peritoneal Macrophages ◽  
Lung Compliance ◽  
Dynamic Lung Compliance

Leukotriene C4 (LTC4) underwent rapid elimination from the circulating blood and was extensively converted to LTD4 within the vascular space of the guinea pig. To mimic the elimination and metabolism of endogenous LTC4 generated during anaphylaxis, 14,15-3H-labeled LTC4 was infused intravenously over a period of 15 min, leading to a recovery in bile of 85% of the infused LT radioactivity within 2 h. Corresponding to the tracer studies, LTD4 and, to a lesser extent, LTC4 were the predominant endogenous cysteinyl LTs in guinea pig bile. The biliary production rate of endogenous LTD4 increased from 0.3 +/- 0.1 to 6.2 +/- 1.8 pmol x min-1 x kg-1 (p less than 0.001) during anaphylactic shock induced by intravenous injection of OVA (0.2 mg/kg) into sensitized guinea pigs. A novel LT biosynthesis inhibitor (MK-886; 10 mg/kg, i.v., 15 min before antigen challenge) suppressed the antigen-induced cysteinyl LT production by greater than 92% (p less than 0.001). This inhibition of systemic LTC4 formation was associated with a complete protection against lethal anaphylactic shock in animals pretreated in addition with the H1 receptor antagonist pyrilamine. Pretreatment with either the inhibitor of LT synthesis or the histamine receptor antagonist reduced the lethality during anaphylactic shock from 100 to 60 and 78%, respectively. In artificially ventilated, pyrilamine-pretreated animals, the antigen-induced decrease in dynamic lung compliance and the rise in hematocrit were significantly reduced (p less than 0.05) by pretreatment with the inhibitor of LT synthesis. Dexamethasone at high doses (10 mg/kg, i.p., once daily for 7 d, or in a single dose of 10 mg/kg, i.v., 3.5 h before challenge) had no inhibitory effect on LT generation during anaphylaxis in vivo. However, in resident peritoneal macrophages, harvested from these dexamethasone-treated sensitized guinea pigs and stimulated with zymosan, both cysteinyl LT and 6-keto-PGF1 alpha formation were strongly suppressed. These studies indicate an important role of cysteinyl LTs in systemic anaphylaxis in vivo and demonstrate the blockade of anaphylactic LT generation by a novel inhibitor of LT biosynthesis (MK-886) but not by dexamethasone.

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.

scholarly journals A pH-Responsive Foam Formulated with PAA/Gemini 12-2-12 Complexes

2021 ◽  
Vol 5 (3) ◽  
pp. 37
Author(s):  
Hernán Martinelli ◽  
Claudia Domínguez ◽  
Marcos Fernández Leyes ◽  
Sergio Moya ◽  
Hernán Ritacco
Keyword(s):  
Surface Tension ◽  
Dynamic Surface Tension ◽  
Foam Formation ◽  
Ph Responsive ◽  
Dynamic Surface ◽  
X Ray ◽  
Equilibrium Surface Tension ◽  
Potential Applications ◽  
The Stability ◽  
Air Interfaces

In the search for responsive complexes with potential applications in the formulation of smart dispersed systems such as foams, we hypothesized that a pH-responsive system could be formulated with polyacrylic acid (PAA) mixed with a cationic surfactant, Gemini 12-2-12 (G12). We studied PAA-G12 complexes at liquid–air interfaces by equilibrium and dynamic surface tension, surface rheology, and X-ray reflectometry (XRR). We found that complexes adsorb at the interfaces synergistically, lowering the equilibrium surface tension at surfactant concentrations well below the critical micelle concentration (cmc) of the surfactant. We studied the stability of foams formulated with the complexes as a function of pH. The foams respond reversibly to pH changes: at pH 3.5, they are very stable; at pH > 6, the complexes do not form foams at all. The data presented here demonstrate that foam formation and its pH responsiveness are due to interfacial dynamics.

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