Biomedical subjects

T Curstedt

Publications and source records attributed to T Curstedt.

At least 73 records · Page 4Linked to original sources

PubMed1993

[Effect of 2 different dosages of a porcine surfactant on pulmonary gas exchange of premature infants with severe respiratory distress syndrome].

BACKGROUND: Doses between 20 and 200 mg/kg body weight (bw) of different surfactant preparations have been recommended in clinical trials for the treatment of neonatal RDS; an optimal dose regimen of surfactant replacement therapy has not yet been defined. Aim of the present pilot study was the evaluation of pulmonary gas exchange in infants with severe RDS following the application of either a high (200 mg/kg bw) or a low (100 mg/kg bw) dose of a natural porcine surfactant (Curosurf). METHODS: 15 neonates were randomized to a high dose regimen, 17 infants to a low dose of surfactant. Apart from a lower 1 minute Apgar in the 100 mg/kg bw group, birth weight, gestational age, sex, 5 minute-Apgar and disease severity (arterial to alveolar oxygenation ratio (a/A-ratio): 0.10 +/- 0.03 [high dose], 0.11 +/- 0.06 [low dose], mean +/- SD) were well matched in both groups. RESULTS: Following surfactant instillation there was a rapid improvement in oxygenation in both groups. The a/A-ratio was slightly higher in the 200 mg/kg bw group during the first 12 hours following surfactant replacement, but statistically this was significantly higher only 4 hours after treatment (0.38 +/- 0.11 vs. 0.24 +/- 0.13, mean +/- SD, p < 0.05). CONCLUSION: The dose of 100 mg/kg bw Curosurf resulted in a rapid improvement in oxygenation and ventilatory requirements; only during the first hours following surfactant replacement there was a slight further improvement with the higher dose of 200 mg/kg bw. The impact of different dose regimens on outcome parameters still has to be defined by a larger clinical trial.

Biological Products↗

PubMed1992

Secondary structure and orientation of the surfactant protein SP-B in a lipid environment. A Fourier transform infrared spectroscopy study.

Attenuated total reflection Fourier transform infrared spectroscopy was used to investigate the secondary structure of the surfactant protein SP-B. Nearly half of the polypeptide chain is folded in an alpha-helical conformation. No significant change of the secondary structure content was observed when the protein is associated to a lipid bilayer of dipalmitoylphosphatidylcholine (DPPC)/phosphatidylglycerol (PG) or of dipalmitoylphosphatidylglycerol (DPPG). The parameters related to the gamma w(CH2) vibration of the saturated acyl chains reveal no modification of the conformation or orientation of the lipids in the presence of SP-B. A model of orientation of the protein at the lipid/water interface is proposed. In this model, electrostatic interactions between charged residues of SP-B and polar headgroups of PG, and the presence of small hydrophobic alpha-helical peptide stretches slightly inside the bilayers, would maintain SP-B at the membrane surface.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1992

[Surfactant treatment of newborn infants with respiratory distress syndrome primarily treated with nasal continuous positive air pressure. A pilot study].

In this pilot study, Curosurf (200 mg/kg) was administrated to 34 patients with the respiratory distress syndrome in nasal-CPAP therapy with FiO2 requirements greater than 0.60 and/or TcPCO2 greater than 8 kPa. The surfactant was instilled during a short period of intubation or in a few cases via an intratracheal catheter (Ch. 6). The age of the patients on surfactant treatment ranged from two to 72 hours. Eighteen patients could be maintained on nasal-CPAP after treatment with Curosurf and only a few complications were seen in these infants. The other 16 patients subsequently required artificial ventilation and had a higher incidence of pulmonary and extrapulmonary complications. On the basis of these observations, we plan a randomized trial to investigate whether, administration of surfactant reduces the need for ventilator treatment and improves the odds for uneventful recovery in this category of patients.

Biological Products↗

PubMed1992

Human surfactant polypeptide SP-B. Disulfide bridges, C-terminal end, and peptide analysis of the airway form.

Human hydrophobic surfactant polypeptide, SP-B, purified from lung tissue by exclusion chromatography in organic solvents, has been characterized. The polypeptide is 79 residues long, has a C-terminal methionine, and contains seven Cys residues. Native human SP-B lacks free thiol groups. Three intrachain disulfide bridges were defined, linking Cys8 to Cys77, Cys11 to Cys71 and Cys35 to Cys46. The remaining Cys48 is concluded to link the protein chains into homodimers via an interchain disulfide to its counterpart in a second SP-B polypeptide. These SS bridges are identical to those in the porcine form and confirm a consestant and unique disulfide pattern for SP-B polypeptides in general.

Amino Acid Sequence↗

PubMed1992

Identification of hydrophobic fragments of alpha 1-antitrypsin and C1 protease inhibitor in human bile, plasma and spleen.

Hydrophobic peptides were isolated from the phospholipid fraction of human bile, plasma and spleen by exclusion chromatography in organic solvents. From plasma, the activation peptide of C1 protease inhibitor was recovered, from spleen the activation peptide of alpha 1-antitrypsin, and from bile, both these peptides, as well as a fragment generated by proteolytic cleavage of alpha 1-antitrypsin six residues N-terminal of the P1-P1' peptide bond. Cleavages in this region inactivate antiproteases but have previously not been reported to occur in vivo. These peptides in human bile may reflect physiological actions in regulation of antiproteolytic activity or bile secretion processes, and/or be of importance for the physicochemical state of cholesterol, phospholipids and bile acids in bile.

Bile↗

PubMed1992

Structure and orientation of the surfactant-associated protein C in a lipid bilayer.

The secondary structure of native and depalmitoylated porcine surfactant-associated protein C (SP-C) was studied by attenuated total reflection Fourier-transform infrared spectroscopy. Both forms of porcine SP-C adopt mainly an alpha-helical conformation. These two forms of the protein were reconstituted in a lipid bilayer. The insertion of the protein in a membrane is associated with an increase of the alpha-helical content. Dichroic measurements show that, in both cases, the long axis of the alpha-helix is oriented parallel to the lipid acyl chains.

Animals↗

PubMed1992

A 2-year follow up of babies enrolled in a European multicentre trial of porcine surfactant replacement for severe neonatal respiratory distress syndrome. Collaborative European Multicentre Study Group.

The postnatal growth, respiratory status and neurodevelopmental outcome of surviving babies enrolled in the first European multicentre trial of porcine surfactant (Curosurf) replacement for severe neonatal respiratory distress syndrome, were assessed at corrected ages of 1 and 2 years. Follow up rates of survivors were 93% at 1 year and 89% at 2 years. Treated and control groups were similar at both 1 and 2 years in terms of physical growth, the prevalence of persistent respiratory symptoms and the occurrence of major and minor disability. Serum antibodies recognising Curosurf and surfactant-anti-surfactant immune complexes were detected in both treated and control babies, the titres showing no difference between groups. Examination of histological lung sections from non-survivors revealed a higher incidence of severe pulmonary interstitial emphysema in control babies than in those treated with surfactant. Surfactant treatment for severe respiratory distress syndrome reduces neonatal mortality and air leaks and is not associated with an increase in disability 2 years later.

Antibodies↗

PubMed1992

Macrophage reaction in rabbit lung following inhalation of iron chloride.

Groups of eight rabbits were inhalation-exposed to iron, 1.4 +/- 0.7 mg/m3 (low Fe), or 3.1 +/- 1.8 mg/m3 (high Fe) as FeCl3 or to filtered air (controls) for 2 months, 5 days/week and 6 hours/day. The alveolar macrophages were increased in number in both exposed groups. Noduli of granular macrophages were found in lungs of all the rabbits in the high-Fe group, in one from the low-Fe group, and in one control rabbit. Especially in the high-Fe group there were prominent changes in the macrophages such as enlarged lysosomes containing fibrous-looking structures, iron-rich inclusions, and densely packed, 5-nm electron-dense granules. The number of cells filled with surfactant-like inclusions as well as a smooth surface was increased in the high-Fe group and the macrophages had enhanced phagocytic capacity. There was an increase in the phospholipid concentration and in the volume density of type II cells in the high-Fe group but the level of phosphatidylcholines was not significantly changed. The fact that Fe3+ affected mainly the alveolar macrophages might be due to the relatively high concentration of iron in these cells caused by the precipitation of iron in their lysosomes.

Administration, Inhalation↗

PubMed1992

Rabbit lung after combined exposure to soluble cobalt and trivalent chromium.

Eight rabbits were exposed to 0.7 +/- 0.4 mg/m3 Co2+ as CoCl2 and 1.2 +/- 0.7 mg/m3 Cr3+ as Cr(NO3)3 (group Co + Cr), eight to 0.6 +/- 0.5 mg/m3 Co2+ (group Co), and eight to filtered air (control group), for 4 months, 5 days/week, and 6 hr/day. All rabbits in group Co + Cr and group Co showed nodular aggregation of alveolar epithelial type II cells. Volume density of the type II cells was significantly higher in group Co + Cr than in group Co and the control group. There was intraalveolar macrophage accumulation in seven rabbits in group Co + Cr, one in group Co, and one in the control group. In lavage fluid the numbers of macrophages and the percentage of these cells with smooth surface and intracellular surfactant-like inclusions were more increased in group Co + Cr than in group Co as were oxidative metabolic and phagocytic activities of the macrophages. Total phospholipids, phosphatidylcholines, and especially 1,2-dipalmitoylphosphatidylcholine was markedly increased in group Co + Cr whereas only 1,2-dipalmitoylphosphatidylcholine was slightly increased in group Co. One mechanism behind the high amount of surfactant phospholipids in group Co + Cr seems to be an enhanced production of surfactant by the type II cells. Another mechanism is probably that Cr3+ reduces the capacity of alveolar macrophages to catabolize surfactant. The results imply that it is important to investigate effects of combinations of cobalt and chromium in the occupational environment.

Animals↗

PubMed1992

Exogenous porcine surfactant (Curosurf) is inactivated by monoclonal antibody to the surfactant-associated hydrophobic protein SP-B.

A monoclonal antibody to the surfactant-associated hydrophobic protein SP-B was added at various concentrations to a standard preparation of porcine surfactant (Curosurf 10 mg/ml), and surface properties were evaluated with pulsating bubble. Retarded adsorption of surfactant was observed at antibody concentrations > or = 0.5 mg/ml and significantly increased values for minimum surface tension were observed at antibody concentrations > or = 1 mg/ml. In vivo effects of the antibody were tested in immature newborn rabbits ventilated with a standardized sequence of insufflation pressures. Animals receiving 0.1 ml surfactant (80 mg/ml) mixed with antibody at concentrations > or = 4 mg/ml had low tidal volumes, poor lung stability in pressure-volume recordings, poor alveolar expansion in histological sections and widespread epithelial necrosis in peripheral airways. Admixtures of IgG had no such effects. We conclude that this monoclonal antibody inactivates exogenous porcine surfactant, probably by preventing fast adsorption of surfactant lipids to the alveolar air-liquid interfaces.

Adsorption↗

PubMed1992

Increased expression of adhesion proteins (MAC-1) and altered metabolic response in human leukocytes exposed to surfactant in vitro.

In this study the modulatory effects of a well-defined surfactant preparation on blood leukocytes were investigated. The expression of the cell surface receptor MAC-1 was analyzed by flow cytofluorometry, and the metabolic response was measured by a chemiluminescence technique. An increase (p less than 0.05) in the MAC-1 receptor expression was observed in the granulocytes but not in the monocytes. There was a decrease in the metabolic response of the leukocytes after stimulation with phorbol myristate acetate (PMA) and a delay (p less than 0.01 for both) in the peak activity. Formyl-methionyl-leucyl-phenylalanine (fMLP) caused an increased peak (p less than 0.01). Thus, the surfactant preparation had a modulatory effect on blood leukocytes with regard to the expression of the cell surface receptor MAC-1 and the metabolic response.

Adolescent↗

PubMed1992

Factors influencing morbidity and mortality in infants with severe respiratory distress syndrome treated with single or multiple doses of a natural porcine surfactant.

In an international multicenter trial infants with clinical and radiological signs of severe RDS (age 2-15 h, birthweight 700-2,000 g, mechanical ventilation, FiO2 greater than or equal to 0.6, no complicating disease) were randomized to receive either a single dose (n = 176) or up to three subsequent doses (n = 167) of a natural porcine surfactant (Curosurf). Using a logistic regression model, the effects of therapy, birthweight, sex, hospital and other clinical factors on survival and various outcome parameters were evaluated. Mortality (13 vs. 21%, p less than 0.05) and the incidence of pneumothorax (9 vs. 18%, p less than 0.01) were significantly lower in the multiple-dose group. Low birthweight, hospital allocation, low Apgar score and initial disease severity were associated with an increased mortality. Low birthweight, hypothermia (admission temperature less than 36 degrees C) and acidosis (pH less than 7.25) prior to surfactant treatment could be identified as risk factors for the development of intracranial hemorrhage.

Biological Products↗

PubMed1992

Alveolar macrophages and lung lesions after combined exposure to nickel, cobalt, and trivalent chromium.

In earlier inhalation exposures of rabbits, nickel increased the production of surfactant by type II cells, with secondary effects on morphology and function of alveolar macrophages. Cobalt induced mainly a nodular growth pattern of the type II cells. Trivalent chromium seemed to impair the capacity of macrophages to catabolize surfactant but did not affect the type II cells. We exposed rabbits by inhalation to combinations of nickel (0.6 mg/m3 as NiCl2) and trivalent chromium [1.2 mg/m3 as Cr(NO3)3] (Ni-Cr), cobalt (0.5 mg/m3 as CoCl2) and nickel (0.5 mg/m3) (Co-Ni), or cobalt (0.5 mg/m3) and chromium (1.2 mg/m3) (Co-Cr) for 4 months, 5 days/week, 6 hr/day. Alveolar macrophages, alveolar type II cells, and lung content of phospholipids were determined. All combined exposures induced more pronounced lung lesions than exposures for each of the metals. Phospholipid concentrations were significantly higher. There were significantly higher percentages of macrophages filled with surfactant-like inclusions and a smooth surface. Accumulations of macrophages in alveoli were more widespread. Chromium potentiated the effects of nickel and cobalt on the type II cells, which led to secondary effects on the macrophages. Nickel potentiated the specific effects of cobalt, i.e., type II cell nodule formation. The result indicates that noxious effects could also be induced in man by combined exposure to nickel, cobalt, and trivalent chromium in concentrations similar to those occurring in some occupational settings.

Animals↗

PubMed1992

Raised plasma hypoxanthine levels as a prognostic sign in preterm babies with respiratory distress syndrome treated with natural surfactant.

Plasma hypoxanthine concentration was measured in twelve preterm babies with respiratory distress syndrome (RDS) treated with 200 mg/kg of a porcine surfactant (Curosurf). Five of the babies died within one week and seven survived the neonatal period. Surviving babies had no significant changes in plasma hypoxanthine concentration throughout a one hour study period following the administration of surfactant. By contrast, in nonsurvivors the mean plasma hypoxanthine concentrations increased from 6.8 mumol/l before surfactant administration to 14.2 mumol/l 15 minutes after surfactant treatment. Survivors had a mean maximal increase in plasma hypoxanthine of 1.9 mumol/l 15-30 min factor surfactant treatment compared with 9.4 mumol/l in nonsurvivors (p < 0.05). The babies who developed intracranial hemorrhage had significantly higher maximal plasma hypoxanthine increase (mean 9.6 mumol/l) compared with babies who did not develop intracranial hemorrhage (mean 1.1 mumol/l) (p < 0.01). The combination of high PaO2 and high hypoxanthine concentration could lead to an increased production of oxygen radicals which might be harmful. We conclude that plasma hypoxanthine concentration may serve as an indicator of the prognosis in preterm babies treated with natural surfactant. Further, it seems important to reduce oxygen supplementation as soon as surfactant is given to possibly limit oxygen radical production.

Biomarkers↗

PubMed1992

Lung protein leakage in respiratory failure induced by a hybridoma making monoclonal antibody to the hydrophobic surfactant-associated polypeptide SP-B.

Adult mice were inoculated intraperitoneally with a hybridoma (8B5E) making monoclonal antibody to the porcine surfactant-associated polypeptide SP-B; this antibody cross-reacts with the corresponding polypeptide in the mouse surfactant system. Respiratory failure, developing 7-9 days after inoculation, was associated with a decrease in lung-thorax compliance determined during artificial ventilation, and an increase in the amount of protein including the specific antibody in lung lavage fluid. There was a statistically significant negative correlation between the compliance and the amount of protein as well as antibody recovered by lung lavage: r (log scale) = -0.69 and -0.82, respectively (P less than 0.01, both), but no decrease in the amount of phospholipids in lung lavage from animals inoculated with the hybridoma. Treatment with a large dose of porcine surfactant (about 320 mg phospholipids/kg body weight) had no positive effect on lung-thorax compliance during artificial ventilation; on the contrary, surfactant-treated animals showed a decrease in compliance similar to that seen in control animals after instillation of a similar volume of saline into the airways. We conclude that respiratory failure developing after inoculation with this hybridoma is probably at least in part mediated by flooding of the airspaces with antibody interfering with surfactant function.

Animals↗

PubMed1992

Randomized European multicenter trial of surfactant replacement therapy for severe neonatal respiratory distress syndrome: single versus multiple doses of Curosurf.

There is now convincing evidence that the severity of neonatal respiratory distress syndrome can be reduced by surfactant replacement therapy; however, the optimal therapeutic regimen has not been defined. This randomized European multicenter trial was designed to determine whether the beneficial effects of a single large dose of Curosurf (200 mg/kg) in babies with severe respiratory distress syndrome (arterial to alveolar oxygen tension ratio approximately 0.10) could be enhanced by using multiple doses of surfactant. Preterm neonates (birth weight 700 to 2000 g) with severe respiratory distress syndrome requiring artificial ventilation with fraction of inspired oxygen greater than or equal to 0.6 were randomized into two groups at an age of 2 to 15 hours. Both groups received the usual dose of Curosurf (200 mg/kg) immediately after randomization. In neonates randomized to receive multiple-dose treatment, two additional doses of Curosurf (100 mg/kg each) were instilled into the airways (12 and 24 hours after the initial dose) provided that the patients still needed artificial ventilation with fraction of inspired oxygen greater than 0.21. In both groups (single dose: n = 176, multiple doses: n = 167) there was a rapid improvement in oxygenation as reflected by a threefold increase in arterial to alveolar oxygen tension ratio within 5 minutes after surfactant instillation (P less than .001), and peak inspiratory pressure and mean airway pressure could be reduced significantly during the first 6 hours after surfactant treatment. In addition, ventilatory requirement (peak inspiratory pressure, ventilatory efficiency index) was reduced in the multiple-dose group 2 to 4 days after randomization (P less than .05 to .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Products↗

PubMed1991

Surfactant protein B: disulfide bridges, structural properties, and kringle similarities.

The disulfide bridges in porcine hydrophobic surfactant protein B (SP-B) were determined. Results show that three intrachain bridges link half-cystine residues 8 and 77, 11 and 71, and 35 and 46, respectively. This gives SP-B an appearance of three loops, a central big loop surrounded by two smaller ones. In the major form of SP-B, the remaining half-cystine, Cys-48, is probably interchain-linked to its counterpart in another molecule, compatible with the existence of dimeric molecules. A minor fraction, with monomeric SP-B but also lacking free thiols, could be due to polypeptides having Cys-57 (instead of Leu in the major form) and hence an additional intrachain bond (Cys-48-Cys-57). Notably, one of the three intrachain bonds common to all SP-B molecules is analogous to one of the disulfide linkages in the kringle structure of complex serine proteases. SP-B and kringles are also similar in size and in positions of half-cystine residues. SP-B and the kringle of coagulation factor XII exhibit 26% residue identity. This structural similarity of SP-B to a binding domain could reflect functional homology, compatible with the notion that SP-B interacts with surfactant anionic phospholipids, which is also in agreement with an SP-B excess of basic residues. Finally, weak similarities between the perform of SP-B and complex serine proteases are also found. This has implications on further possible relationships between kringles, serine proteases, and antiproteases.

Amino Acid Sequence↗

PubMed1991

Canine hydrophobic surfactant polypeptide SP-C. A lipopeptide with one thioester-linked palmitoyl group.

The amino acid sequence and the posttranslational modification of the hydrophobic surfactant polypeptide SP-C from canine, rabbit and bovine lungs were established by direct sequence analysis and plasma-desorption time-of-flight mass spectrometry. The results reveal that canine SP-C has only one cysteine residue which, however, is palmitoylated, like the two Cys residues in other characterized SP-C molecules. In addition, canine SP-C is N-terminally truncated, with only 34 amino acid residues in its longest form. Thus, SP-C molecules can apparently vary to some extent in the N-terminal lipid-modified part, whereas the extremely hydrophobic middle and C-terminal parts are well conserved.

Amino Acid Sequence↗