Biomedical subjects

T Curstedt

Publications and source records attributed to T Curstedt.

At least 37 records · Page 2Linked to original sources

PubMed1998

Comparison of rapid bolus instillation with simplified slow administration of surfactant in lung lavaged rats.

The aim of this study was to compare the effects of modified porcine surfactant (Curosurf) given either by a simplified slow delivery technique or by the standard bolus method, on pulmonary gas exchange, lung mechanics, and surfactant distribution in rats with respiratory failure produced by lung lavage. Twelve rats with respiratory failure induced by lung lavage received 200 mg x kg(-1) body weight (b.w.) of tagged porcine surfactant, either by the standard bolus delivery technique or by a simplified 1-min intratracheal infusion method, not requiring interruption of mechanical ventilation. Cardiovascular parameters, arterial blood gases, and pulmonary mechanics were measured repeatedly. Surfactant distribution was also measured by dye-tagged microbead spheres. After surfactant administration, there were no overall major differences between groups in mean heart rate, blood pressure, arterial blood gases, dynamic lung compliance, respiratory system resistance, and pulmonary distribution of exogenous surfactant. However, after 180 min pulmonary gas exchange was better and compliance higher in the bolus than the 1-min infusion group. A transient decrease in blood pressure and heart rate was observed in the bolus group; this side effect was not seen in animals treated with the simplified 1-min infusion method. We conclude that in rats subjected to lung lavage, the infusion of porcine surfactant by a simplified 1-min procedure produced similar short-term effects compared to the same dose of surfactant given by the bolus method. We speculate that tracheal bolus dosing is highly effective and might be the preferable delivery method for porcine surfactant. Dosing by the simplified method described appears less effective, but since no significant differences were observed, and since it produced less acute adverse effects, it could be used when clinical circumstances preclude rapid delivery.

Animals↗

PubMed1998

Pulmonary surfactant-associated polypeptide C in a mixed organic solvent transforms from a monomeric alpha-helical state into insoluble beta-sheet aggregates.

In the 35-residue pulmonary surfactant-associated lipopolypeptide C (SP-C), the stability of the valyl-rich alpha-helix comprising residues 9-34 has been monitored by circular dichroism, nuclear magnetic resonance, and Fourier transform infrared spectroscopy in both a mixed organic solvent and in phospholipid micelles. The alpha-helical form of SP-C observed in freshly prepared solutions in a mixed solvent of CHCl3/CH3OH/0.1 M HCl 32:64:5 (v/v/v) at 10 degrees C undergoes within a few days an irreversible transformation to an insoluble aggregate that contains beta-sheet secondary structure. Hydrogen exchange experiments revealed that this conformational transition proceeds through a transition state with an Eyring free activation enthalpy of about 100 kJ mol(-1), in which the polypeptide segment 9-27 largely retains a helical conformation. In dodecylphosphocholine micelles, the helical form of SP-C was maintained after seven weeks at 50 degrees C. The alpha-helical form of SP-C thus seems to be the thermodynamically most stable state in this micellar environment, whereas its presence in freshly prepared samples in the aforementioned mixed solvent is due to a high kinetic barrier for unfolding. These observations support a previously proposed pathway for in vivo synthesis of SP-C through proteolytic processing from a 21-kDa precursor protein.

Amino Acid Sequence↗

PubMed1998

Acute effects on systemic circulation after intratracheal instillation of Curosurf or Survanta in surfactant-depleted newborn piglets.

Systemic vasodilatation in surfactant-depleted newborn piglets is induced by 200 mg/kg of modified porcine lung surfactant (Curosurf). The aim of this investigation was to study whether this effect is dependent on dose and could further be induced by instillation of a bovine surfactant preparation (Survanta). Twenty-two 3-5-d old piglets were subjected to repeated saline lung lavage and then randomized to one of three groups. Instillation of either Curosurf l00 mg/kg (n=8), Survanta l00 mg/kg (n=7) or Curosurf 200 mg/kg (n=7) was performed through the endotracheal tube. Systemic vascular resistance decreased 7 (+/-4)%, 15 (+/-12)% and 18 (+/-6)% in the three groups, respectively (p < 0.05 in all three groups). A significant difference between the high and low dose Curosurf groups was found (p < 0.05), whereas no significant difference was seen between the Curosurf 100 mg group and the Survanta group. The decrease in vascular resistance was compensated by an increase in cardiac output, resulting in a stable mean arterial blood pressure. In conclusion, both Curosurf and Survanta induce a significant decrease in systemic vascular resistance in surfactant-depleted newborn piglets. A more pronounced effect was observed after 200 mg/kg than after 100mg/kg of Curosurf.

Animals↗

PubMed1998

Synthetic surfactant protein analogues.

Surfactant preparations for the treatment of respiratory distress syndrome (RDS) that contain phospholipids and small amounts of the two hydrophobic proteins, SP-B and SP-C, are presently obtained from animal lungs. Since structural information about SP-B and SP-C is available, it appears possible to design analogues that can replace the native proteins in synthetic surfactants. SP-C contains a single helix, but analogues with the poly-Val sequence of the native molecule do not fold into a native-like alpha-helical conformation. However, replacement of all Val with Leu yields efficient folding into a helical structure and Leu-based SP-C analogues effectively accelerate spreading of surfactant lipids and exhibit some physiological activity in animal models of RDS. The inferior in vivo activity of synthetic surfactants containing SP-C only compared to that of surfactant preparations derived from natural sources may be caused by a lack of covalently linked palmitoyl groups in the analogues and/or absence of SP-B. SP-B is significantly larger than SP-C and has a tertiary fold of several amphipathic helices in a dimeric structure. A single simplified amphipathic helical peptide containing only Leu and Lys does not mimic the surface properties of SP-B in vitro. These circumstances make the design of SP-B analogues from solely structural considerations less likely to be successful than in the case of SP-C.

Drug Design↗

PubMed1997

Reverse-phase HPLC of the hydrophobic pulmonary surfactant proteins: detection of a surfactant protein C isoform containing Nepsilon-palmitoyl-lysine.

A reverse-phase HPLC protocol for analysis of strictly hydrophobic peptides and proteins was developed. Peptide aggregation is minimized by using only 25-40% water in methanol or ethanol as initial solvents and subsequent elution with a gradient of propan-2-ol. Analysis of the pulmonary surfactant-associated proteins B (SP-B) and C (SP-C) with this method reveals several features. (1) SP-B and SP-C retain their secondary structures and separate by about 15 min over a 40 min gradient. SP-B is more hydrophilic than SP-C, which in turn behaves chromatographically like palmitoyl-ethyl ester. (2) SP-C exhibits isoforms additional to the major form characterized previously, which contains two thioester-linked palmitoyl groups. The isoforms now observed contain one or three palmitoyl moieties and constitute together 15-20% of the major form. The tripalmitoylated species contains a palmitoyl group linked to the epsilon-amino group of Lys-11, as concluded from the elution position,MS and amino acid sequence analysis. The tripalmitoylated form increases relative to the dipalmitoylated form on incubation of SP-C ina phospholipid environment. An Nepsilon-bound palmitoyl moiety constitutes a third mode of fatty acyl modification of proteins, in addition to the established Nalpha-bound myristoyl groups and S-bound palmitoyl chains. (3) The dimeric structure of SP-B, lacking covalent modifications, is confirmed by MS detection of the dimer. No SP-B isoforms were detected. (4) Denatured, non-helical SP-C can be distinguished chromatographically from the native alpha-helical peptide. (5) HPLC of SP-C at 60-75 degrees C reveals an isoform containing an extra 14 Da moiety compared with the main form. This is concluded to arise from inadvertent methyl esterification of the C-terminal carboxy group. In conclusion, this HPLC method affords a sensitive means of assessing modifications and conformations of SP-B or SP-C in different disease states and before functional studies. It might also prove useful for analysis of other strictly hydrophobic polypeptides.

Animals↗

PubMed1997

Molecular structures and interactions of pulmonary surfactant components.

The dominating functional property of pulmonary surfactant is to reduce the surface tension at the alveolar air/liquid interface, and thereby prevent the lungs from collapsing at the end of expiration. In addition, the system exhibits host-defense properties. Insufficient amounts of pulmonary surfactant in premature infants causes respiratory distress syndrome, a serious threat which nowadays can be effectively treated by airway instillation of surfactant preparations. Surfactant is a mixture of many molecular species, mainly phospholipids and specific proteins, surfactant protein A (SP-A), SP-B, SP-C and SP-D. SP-A and SP-D are water-soluble and belong to the collectins, a family of large multimeric proteins which structurally exhibit collagenous/lectin hybrid properties and functionally are Ca2+-dependent carbohydrate binding proteins involved in innate host-defence functions. SP-A and SP-D also bind lipids and SP-A is involved in organization of alveolar surfactant phospholipids. SP-B belongs to another family of proteins, which includes also lipid-interacting polypeptides with antibacterial and lytic properties. SP-B is a 17.4-kDa homodimer and each subunit contains three intrachain disulphides and has been proposed to contain four amphipathic helices oriented pairwise in an antiparallel fashion. SP-A, SP-B and SP-D all have been detected also in the gastrointestinal tract. SP-C, in contrast, appears to be a unique protein with extreme structural and stability properties and to exist exclusively in the lungs. SP-C is a lipopeptide containing covalently linked palmitoyl chains and is folded into a 3.7-nm alpha-helix with a central 2.3-nm all-aliphatic part, making it perfectly suited to interact in a transmembranous way with a fluid bilayer composed of dipalmitoylglycerophosphocholine, the main component of surfactant. Homozygous genetic deficiency of proSP-B causes lethal respiratory distress soon after birth and is associated with aberrant processing of the precursor of SP-C. This review focuses on the chemical composition, structures and interactions of the pulmonary surfactant, in particular the associated proteins.

Animals↗

PubMed1997

Surfactant prevents quartz induced down-regulation of complement receptor 1 in human granulocytes.

Quartz is known to induce an inflammatory response in the alveolar space by recruitment of different effector cells. We investigated the interaction between granulocytes and quartz with respect to expression of complement receptor type 1 (CR1) and CR3, with and without the presence of surfactant. Granulocytes from hemolyzed blood were stimulated by N-formyl-methionyl-leucyl-phenylalanine (fMLP), which mobilize the intracellular pool of CR1 to the surface, and the mean fluorescence intensity (MFI) measured by cytofluorometry was 47.4 (46-63.6) (median; interquartile range). Quartz exposure reduced the CR1 expression to 23.2 (22.8-30.6) MFI units (P < 0.01), a porcine surfactant preparation added during quartz exposure abolished the down-regulation completely, 47.7 (43.2-62.3) MFI units (P < 0.001). Similar results were obtained after preincubation of the cells with surfactant followed by quartz exposure. No significant influence on CR1 expression was found by a synthetic lipid mixture, nor was the CR3 expression affected. In conclusion, this study demonstrates that the presence of surfactant inhibits quartz induced down-regulation of CR1 on activated granulocytes.

Adolescent↗

PubMed1997

Surfactant improves lung function and mitigates bacterial growth in immature ventilated rabbits with experimentally induced neonatal group B streptococcal pneumonia.

AIMS: To study the influence of surfactant on lung function and bacterial proliferation in immature newborn rabbits with experimental group B streptococcal (GBS) pneumonia. METHODS: Preterm rabbit fetuses (gestational age 28 days) underwent tracheotomy and were mechanically ventilated in a warmed body plethysmograph that permitted measurement of lung-thorax compliance. Fifteen minutes after the onset of ventilation the animals received either GBS or saline intratracheally; at 30 minutes, a bolus of saline or 200 mg/kg of a porcine surfactant (Curosurf) was administered via the airway. Bacterial proliferation was evaluated in lung homogenate at the end of the experiments and the results expressed as mean log10 cfu/g lung (SD). Animals receiving only saline (n = 20) or saline and surfactant (n = 20) served as controls. RESULTS: The average survival time was about three hours in all groups. Infected animals receiving surfactant (n = 22) had significantly less bacterial growth (9.09 (0.45) vs 9.76 (0.91)) and improved lung function (compliance: 0.61 (0.14) vs 0.34 (0.19) ml/kg. cm H2O) than infected rabbits receiving saline at 30 minutes (n = 22). CONCLUSION: Surfactant improves lung function and mitigates bacterial growth in preterm rabbits infected with group B streptococci.

Animals↗

PubMed1997

Biophysical and physiological properties of a modified porcine surfactant enriched with surfactant protein A.

Surfactant protein A (SP-A), a major protein component of natural pulmonary surfactant, is absent in exogenous surfactants currently used in clinical practice. We investigated the physical and physiological properties of one of these modified natural surfactants (Curosurf) after enrichment with 5% SP-A (SP-A-Curosurf). A pulsating bubble system was used for in vitro assessments and ventilated newborn rabbits for evaluation of in vivo effects. In the presence of various potential inhibitors (meconium 5 mg.mL-1, fibrinogen 5 mg.mL-1, albumin 25 mg.mL-1, or whole serum proteins 25 mg.mL-1), Curosurf at a concentration of 5 mg.mL-1 was inactivated while SP-A-Curosurf and natural porcine surfactant at the same concentration had normal maximum and minimum surface tension. This protective effect of SP-A was calcium dependent. In immature newborn rabbits, the improvement of lung-thorax compliance observed after treatment with 100 mg.kg-1 of SP-A-Curosurf was equivalent to that obtained with 200 mg.kg-1 of Curosurf. Similarly, in near-term newborn rabbits with respiratory failure induced by instillation of fibrinogen via the airways, the increase in compliance after administration of 100 mg.kg-1 of SP-A-Curosurf corresponded to that seen after treatment with 200 mg.kg-1 of Curosurf, whereas Curosurf at a dose of 100 mg.kg-1 had no substantial effect. Our data thus indicate that surfactant protein A increases the resistance of Curosurf to inactivation under in vivo conditions.

Albumins↗

PubMed1997

Nitric oxide contributes to surfactant-induced vasodilation in surfactant-depleted newborn piglets.

To investigate whether nitric oxide (NO) is involved in surfactant-induced systemic and pulmonary vasodilatation in newborn piglets with surfactant deficiency, 2-6-d-old piglets were subjected to repeated saline lung lavages. They were then randomly assigned to one of two groups (seven in each group): the N(omega)-nitro-L-arginine methyl ester (L-NAME) group received 3 mg/kg L-NAME i.v. 45 min before endotracheal instillation of 200 mg/kg porcine surfactant; the saline group received saline i.v. at the same time point, and instillation of 200 mg/kg surfactant. Mean arterial blood pressure, systemic vascular resistance, pulmonary arterial pressure, and pulmonary vascular resistance increased significantly after injection of L-NAME (all p < 0.01), whereas the cardiac index decreased significantly (p < 0.05). Saline injection did not change any variable. Significant decreases in mean arterial blood pressure (from a mean +/- SD of 66 +/- 10 to 53 +/- 9 mm Hg, p < 0.01), pulmonary arterial pressure (from 29 +/- 6 to 23 +/- 6 mm Hg, p < 0.01), and systemic vascular resistance (from 0.40 +/- 0.13 to 0.33 +/- 0.12 mm Hg/mL/min/kg, p < 0.05) were observed only in the saline group after surfactant instillation, whereas the decrease in pulmonary vascular resistance was not significant after surfactant instillation (p = 0.06). In contrast to the saline group, these variables were not modified in the L-NAME group after surfactant instillation. We conclude that the vasodilatory effect of porcine surfactant instillation in newborn piglets with surfactant deficiency is associated with activation of NO synthase.

Animals↗

PubMed1997

Manual ventilation with a few large breaths at birth compromises the therapeutic effect of subsequent surfactant replacement in immature lambs.

The reason why some infants with respiratory distress syndrome fail to respond to surfactant, or respond only transiently, is incompletely understood. We hypothesized that resuscitation with large breaths at birth might damage the lungs and blunt the effect of surfactant. Five pairs of lamb siblings were delivered by cesarean section at 127-128 d of gestation. One lamb in each pair was randomly selected to receive six manual inflations of 35-40 mL/kg ("bagging") before the start of mechanical ventilation, a volume roughly corresponding to the inspiratory capacity of lamb lungs after prophylactic surfactant supplementation. Both siblings were given rescue porcine surfactant, 200 mg/kg, at 30 min of age. Blood gases and deflation pressure-volume (P-V) curves of the respiratory system were recorded until the lambs were killed at 4 h. The P-V curves became steeper after surfactant in the control group, but no such effect was seen in those subjected to bagging. At 4 h, inspiratory capacity and maximal deflation compliance were almost three times higher (p < 0.01) in the controls than in the bagged lambs. The latter were also more difficult to ventilate and tended to have less well expanded alveoli and more widespread lung injury in histologic sections. We conclude that a few inflations with volumes that are probably harmless in other circumstances might, when forced into the surfactant-deficient lung immediately at birth, compromise the effect of subsequent surfactant rescue treatment. Our findings challenge current neonatal resuscitation practice of rapidly establishing a normal lung volume by vigorous manual ventilation.

Animals↗

PubMed1996

The 21-residue surfactant peptide (LysLeu4)4Lys(KL4) is a transmembrane alpha-helix with a mixed nonpolar/polar surface.

The 21-residue peptide KLLLLKLLLLKLLLLKLLLLK (KL4) has been synthesized and analyzed regarding its secondary structure and orientation in lipid environments. Fourier transform infrared and circular dichroism spectroscopy shows that the peptide exhibits approximately 80% alpha-helical content both in dodecylphosphocholine micelles and in 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/phosphatidylglycerol (PG) 7:3 (w/w) bilayers. The positively charged lysine residues are evenly distributed over the entire, otherwise nonpolar, circumference of the helix. This is in sharp contrast to the uneven distribution of polar and nonpolar residues in amphipathic helices. Fourier transform infrared spectroscopy of the peptide inserted in DPPC/PG bilayers shows that the helical axis is oriented parallel to the lipid acyl chains. These data do not support a previous hypothesis that the KL4 peptide interacts with peripheral parts of a phospholipid monolayer and mimics the pulmonary surfactant protein SP-B, which is composed of several amphipathic alpha-helices. KL4 accelerates the spreading of phospholipid mixtures at an air/water interface but does so less efficiently than other transmembranous helical polypeptides studied.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1996

Long-term cycling of surfactant films in Wilhelmy balance.

Surface properties of porcine surfactant were observed during long-term cycling in Wilhelmy balance. Various amounts of surfactant were applied onto the surface as dry particles or droplets, or were suspended in the hypophase, and the films generated by this material were subjected to 50% cyclic compression at a rate of 1 cycle per min. Film spreading was faster from a droplet than from a particle of lyophilized surfactant, but the "stable period" during which minimum surface tension of the compressed film remained below 5 mN/m was significantly longer for the dry material. For surfactant suspensions the period of film "refinement", defined as the number of cycles required to reduce minimum surface tension to a level below 5 mN/m, was inversely correlated with the concentration of surfactant in the hypophase. Thirteen batches of porcine surfactant, used successfully in clinical trials for treatment of neonatal respiratory distress syndrome, were evaluated in the same system suspended in the hypophase at a concentration of 0.5 mg/ml. Films adsorbed from these batches had a median refinement period of 4 cycles, and a median stable period of 2160 cycles (36 h). In the same assay system, surfactant activity was inhibited in a dose-dependent manner by serum, fibrinogen, meconium, and bilirubin, but the specific inhibitory activity was significantly higher for bilirubin than for the other substances tested.

Analysis of Variance↗

PubMed1996

Surfactant treatment in experimental Escherichia coli pneumonia.

BACKGROUND: Deterioration of lung function in bacterial pneumonia may in part be due to inactivation of endogenous surfactant. We investigated the effects of surfactant treatment on gas exchange and lung morphology in an experimental model of pneumonia caused by Escherichia coli. METHODS: A total of 117 adult rats received via the trachea 2 ml/kg body weight of a standard suspension of Escherichia coli (4 x 10(9) bacteria/ml). After 2-3 days, 31 of the infected animals showed symptoms of respiratory failure with PaO2 < 27 kPa during ventilation with 100% O2. All these animals were kept in a multi-plethysmograph system and ventilated for 45 min with a tidal volume of 6 ml/kg, a frequency of 30/min, an inspiration/expiration ratio of 1:1, and a positive end-expiratory pressure of 0.2 kPa. After 15 min of mechanical ventilation, animals were divided in three treatment groups, receiving via the airways (1) no material, (2) normal saline (2 ml/kg), or (3) Curosurf, 80 mg/ml (2 ml/kg). Ten healthy animals served as controls. Lung-thorax compliance and blood gases were measured 15 and 30 min after surfactant treatment. After the period of ventilation, animals were killed, and the left lung was weighed and fixed in formalin for histological examination. The right lung was washed in situ with normal saline via the tracheal tube. Total phospholipids, and levels of phosphatidylcholine (PC) and protein in lavage fluid were determined. RESULTS: In comparison with pre-treatment values, average PaO2 at 30 min was increased by 76% in animals receiving Curosurf (P < 0.01), but did not improve in the other groups. The left lung weight/body weight ratio showed a nearly 3-fold increase in infected animals in comparison with normal controls. There was also a 3-fold increase in the protein content of lung lavage fluid from infected rats, but values for total phospholipids and PC content were unchanged in animals not receiving surfactant. Histological examination of the lungs showed wide-spread non-specific pneumonia in infected animals, but no difference in alveolar air expansion between surfactant-treated and non-treated ones. CONCLUSION: Surfactant replacement significantly improves oxygenation in rats with E. coli pneumonia, without affecting lung-thorax compliance during mechanical ventilation or alveolar expansion pattern in lungs fixed by conventional methods.

Animals↗

PubMed1996

Synthetic protein analogues in artificial surfactants.

Today, airway instillation of surfactant preparations is a generally used treatment for respiratory distress syndrome in premature infants. Most commercially available surfactants are purified from animal lungs and contain lipids, mainly phospholipids, and about 2% of the hydrophobic surfactant proteins B and C (SP-B and SP-C). During the last half-decade the main structural properties of these proteins have been clarified and this knowledge now makes it possible to design synthetic analogues for future use in artificial surfactants.

Drug Design↗

PubMed1996

Exogenous surfactant improves ventilation efficiency and alveolar expansion in rats with meconium aspiration.

The pathogenesis of neonatal meconium aspiration syndrome (MAS) may involve inactivation of endogenous surfactant, and data from clinical pilot studies indicate that treatment with exogenous surfactant may alleviate respiratory failure in babies with MAS. We studied ventilation efficiency after treatment with a modified porcine surfactant in experimental meconium aspiration. Adult rats were anesthetized and tracheotomized, and received via a tracheal cannula from 4 to 6 ml/kg body weight of a saline suspension of human meconium (25 mg [dry weight]/ml). After 30 min of ventilation with 100% oxygen, the animals were in respiratory failure, with dynamic lung-thorax compliance < 0.5 ml/cm H2O/kg and PaO2 < 8 kPa (60 mm Hg). Animals were then allocated to: (1) immediate treatment with surfactant (200 mg/kg); (2) treatment with surfactant (200 mg/kg 3 h later; or (3) a control group not receiving surfactant. All animals were ventilated for 6 h with variable FIO2 and peak inspiratory/positive end-expiratory pressure (PIP/PEEP). In the control group, six of 12 animals died of respiratory failure with hypoxemia and acidosis despite ventilation with 100% oxygen and high mean airway pressure (> 20 cm H2O). The lungs of all animals in this group showed severe atelectasis, influx of neutrophils, edema, and hyaline membranes. In contrast, animals allocated to immediate or late surfactant treatment had lower mortality (one of seven and two of eight, respectively), a reduction of oxygen supply by 30%, and a decrease in mean airway pressure of 3 to 4 cm H2O. This was associated with a > 50% increase in static lung volume at 40 cm H2O inflation and 10 cm H2O deflation pressure and improved alveolar expansion in histologic sections. Hyaline membranes tended to be less prominent in surfactant-treated animals than in controls. We conclude that both early and late treatment with surfactant is effective in this animal model of MAS.

Animals↗

PubMed1996

Hemodynamics and tissue blood flow after porcine surfactant replacement in surfactant-depleted newborn piglets.

In 22 newborn piglets we studied the effect of hypovolemia or hypoxemia on hemodynamics and regional blood flow after instillation of porcine surfactant. Surfactant deficiency was obtained by repeated lung lavage, and blood flow measurements were carried out using radioactive microspheres. Three groups of piglets were studied, controls (n = 8), hypovolemia (n = 7), and hypoxemia (n = 7). Three to five minutes after instillation of surfactant, mean arterial blood pressure decreased significantly in all three groups with a mean decrease (+/- SD) of 31(+/- 12), 33(+/- 9), and 29(+/- 9) mm Hg, respectively (p < 0.01 in all three groups). Systemic vascular resistance decreased significantly in all three groups immediately after surfactant instillation (p < 0.01) and returned to presurfactant level after 60 min. Blood flow did not change after surfactant instillation in any of the three groups, in neither skin, muscle, pancreas, brain, nor retina. In liver, kidney, intestine, and choroidea there was a decrease in blood flow immediately after instillation with return to presur-factant levels within 60 min. Hypoxemia or hypovolemia before surfactant instillation did not increase the hemodynamic instability. The decrease in mean arterial blood pressure was caused by a vasodilation and not by a reduced cardiac output.

Animals↗

PubMed1995

Secondary structure and biophysical activity of synthetic analogues of the pulmonary surfactant polypeptide SP-C.

Native pulmonary-surfactant-associated lipopolypeptide SP-C, its chemically depalmitoylated form and several synthetic analogues lacking the palmitoylcysteine residues were analysed for secondary structure in phospholipid micelles and for biophysical activity in 1,2-dipalmitoyl-sn-glycero-3- phosphocholine/phosphatidylglycerol/palmitic acid (68:22:9, by wt.). Compared with the native molecule, with the entire poly-valyl part in a known alpha-helical conformation, depalmitoylated SP-C was found to be still mainly alpha-helical, but with an approx. 20% decrease in the helical content. A synthetic hybrid polypeptide where the entire poly-valyl alpha-helical part of native SP-C had been replaced with the amino acid sequence of a transmembrane helix of bacteriorhodopsin is also predominantly alpha-helical. In contrast, synthetic SP-C analogues lacking only the palmitoyl groups, by replacement of the palmitoylcysteine residues with cysteine, phenylalanine or serine, or lacking the positively charged amino acids by replacement with alanine, are considerably less alpha-helical than both native and depalmitoylated SP-C. The data indicate that the SP-C palmitoyl groups are important for maintenance of the alpha-helical conformation in parts of the polypeptide, and that the poly-valyl alpha-helical conformation is not fully formed in synthetic SP-C polypeptides. Furthermore, the helical structure of both native and depalmitoylated SP-C in dodecylphosphocholine micelles is very resistant to thermal denaturation, exhibiting ordered structure at 90 degrees C. The alpha-helical content grossly parallels the peptide-induced acceleration of the spreading of phospholipids at an air/water interface and the increase of surface pressure. The data suggest that the alpha-helical conformation itself, rather than just the covalent structure, is of prime importance for the biological function of synthetic pulmonary-surfactant peptides.

Amino Acid Sequence↗