Biomedical subjects

Tore Curstedt

Publications and source records attributed to Tore Curstedt.

9 recordsLinked to original sources

PubMed2006

New synthetic surfactant - how and when?

Animal-derived surfactant preparations are very effective in the treatment of premature infants with respiratory distress syndrome but they are expensive to produce and supplies are limited. In order to widen the indications for surfactant treatment there is a need for synthetic preparations, which can be produced in large quantities and at a reasonable cost. However, development of clinically active synthetic surfactants has turned out to be more complicated than initially anticipated. The hydrophobic surfactant proteins, SP-B and SP-C, which are involved in the adsorption of surface-active lipids to the air-liquid interface of the alveoli and increase alveolar stability, are either too big to synthesize, structurally complex or unstable in pure form. A new generation of synthetic surfactants containing simplified phospholipid mixtures and small amounts of peptides replacing the hydrophobic proteins is currently under development and will in the near future be introduced into the market. However, more trials need to be performed before any conclusions can be drawn about the effectiveness of these synthetic surfactants in relation to natural animal-derived preparations.

Animals↗

PubMed2006

Structure and influence on stability and activity of the N-terminal propeptide part of lung surfactant protein C.

Mature lung surfactant protein C (SP-C) corresponds to residues 24-58 of the 21 kDa proSP-C. A late processing intermediate, SP-Ci, corresponding to residues 12-58 of proSP-C, lacks the surface activity of SP-C, and the SP-Ci alpha-helical structure does not unfold in contrast to the metastable nature of the SP-C helix. The NMR structure of an analogue of SP-Ci, SP-Ci(1-31), with two palmitoylCys replaced by Phe and four Val replaced by Leu, in dodecylphosphocholine micelles and in ethanol shows that its alpha-helix vs. that of SP-C is extended N-terminally. The Arg-Phe part in SP-Ci that is cleaved to generate SP-C is localized in a turn structure, which is followed by a short segment in extended conformation. Circular dichroism spectroscopy of SP-Ci(1-31) in microsomal or surfactant lipids shows a mixture of helical and extended conformation at pH 6, and a shift to more unordered structure at pH 5. Replacement of the N-terminal hexapeptide segment SPPDYS (known to constitute a signal in intracellular targeting) of SP-Ci with AAAAAA results in a peptide that is mainly unstructured, independent of pH, in microsomal and surfactant lipids. Addition of a synthetic dodecapeptide, corresponding to the propeptide part of SP-Ci, to mature SP-C results in slower aggregation kinetics and altered amyloid fibril formation, and reduces the surface activity of phospholipid-bound SP-C. These data suggest that the propeptide part of SP-Ci prevents unfolding by locking the N-terminal part of the helix, and that acidic pH results in structural disordering of the region that is proteolytically cleaved to generate SP-C.

Animals↗

PubMed2006

Polymyxin B/pulmonary surfactant mixtures have increased resistance to inactivation by meconium and reduce growth of gram-negative bacteria in vitro.

Pulmonary surfactant is inactivated in meconium aspiration syndrome and neonatal pneumonia. Development of an exogenous surfactant less sensitive to inactivation might be useful for treating these diseases. We investigated in vitro whether addition of the cationic cyclic membrane cross-linking peptide polymyxin B (PxB) and/or calcium chloride (CaCl2) to modified porcine surfactant Curosurf increases resistance to meconium-induced inactivation of surface activity while antimicrobial activity of PxB is maintained. To study bacterial proliferation, Escherichia coli, group B streptococci (GBS), or Staphylococcus aureus were incubated 0-5 h in saline or in meconium in the presence or absence of Curosurf with or without PxB. PxB and CaCl2 improved spreading and adsorption of Curosurf. Curosurf plus CaCl2/PxB needed a 4-fold increase of meconium concentration to increase dynamic surface tension significantly compared with Curosurf plus CaCl2 alone, indicating that PxB further increases the resistance of Curosurf to meconium-induced inactivation. Meconium alone like meconium/Curosurf promoted growth of E. coli and GBS, but addition of Curosurf/PxB or PxB alone significantly reduced the growth of E. coli. Biophysical and antibacterial properties of Curosurf and PxB may be combined into a useful adjunct in the treatment of neonatal Gram-negative pneumonia and/or meconium aspiration syndrome.

Animals↗

PubMed2005

New synthetic surfactants--basic science.

The hydrophobic surfactant proteins, SP-B and SP-C, promote adsorption of surface-active lipids to the air-liquid interface of the alveoli and are essential for alveolar stability and gas exchange. Synthetic surfactant preparations must contain at least one of these hydrophobic proteins, or analogs thereof, to have optimal effects when administered into the airways of patients with lung diseases. However, development of clinically active artificial surfactants has turned out to be more complicated than initially anticipated since the native hydrophobic proteins are structurally complex or unstable in pure form. The proteins have been replaced by different analogs which have the right conformation without forming oligomers. Increased understanding of the surfactant proteins will hopefully lead to development of effective synthetic surfactants which can be produced in large quantities for treatment of a wide range of respiratory disorders. Furthermore, the lipid composition seems to be important, as well as a high lipid concentration in the suspension. For successful treatment of many respiratory diseases, it is also desirable that the synthetic surfactant resists inactivation by plasma components leaking into the alveoli.

Animals↗

PubMed2005

Spontaneous breathing or mechanical ventilation alters lung compliance and tissue association of exogenous surfactant in preterm newborn rabbits.

In preterm infants with respiratory distress syndrome, surfactant administration followed by immediate extubation to spontaneous breathing with nasal continuous positive airway pressure reduces the need for mechanical ventilation. With this treatment approach, repeated doses of surfactant are rarely indicated. We used a rabbit model to test the hypothesis that exogenous surfactant therapy followed by spontaneous breathing results in a more sustained initial treatment response compared with treatment followed by mechanical ventilation. Preterm rabbits (gestational age 28.5 d) were treated with pharyngeal deposition of 200 mg/kg radiolabeled surfactant (14C-Curosurf) and randomized to 4 h of spontaneous breathing or mechanical ventilation or to a control group, killed immediately after surfactant administration. With pharyngeal deposition, 46 +/- 10% (mean +/- SEM) of the administered surfactant reached the lungs. The dynamic lung-thorax compliance was higher in spontaneously breathing compared with mechanically ventilated animals (median, 9.9 and 0.75 ml x cm H2O(-1) x kg(-1), respectively; p < 0.05). The relative distribution of 14C-Curosurf in bronchoalveolar lavage fluid and homogenized lung tissue showed a higher degree of tissue association in the spontaneously breathing animals [53 +/- 4 versus 26 +/- 3% (mean +/- SEM)] than in mechanically ventilated animals (p < 0.01), the latter figure being very similar to that of the control group (25 +/- 5%). There was a higher degree of lipid peroxidation and fewer microbubbles in bronchoalveolar lavage fluid from mechanically ventilated animals. We conclude that the initial lung tissue association of exogenous surfactant is impaired by mechanical ventilation. This is associated with a reduction of dynamic compliance and evidence of increased surfactant inactivation.

Animals↗

PubMed2005

Surfactant protein C: basics to bedside.

Development of clinically active synthetic surfactants has turned out to be more complicated than initially anticipated. Surfactant protein analogues must have the right conformation without forming oligomers. Furthermore, the lipid composition, as well as a high lipid concentration in the suspension seem to be important. For successful treatment of many respiratory diseases, it is desirable that the synthetic surfactant may stabilize the alveoli at end-expiration and may resist inactivation by components leaking into the alveoli.

Animals↗

PubMed2004

Incomplete protection by prophylactic surfactant against the adverse effects of large lung inflations at birth in immature lambs.

OBJECTIVE: To investigate whether preceding surfactant instillation prevents the harmful effect of large lung inflations at birth in immature lambs, and, if not, to find out for how long the immature lung remains sensitive to large inflations. DESIGN: In an exploratory study, 12 preterm lambs given surfactant at birth were randomized to receive five large lung inflations at four different times: at birth just before or immediately after surfactant treatment; at 10 min; or at 60 min of age. In a confirmatory study, 10 pairs of preterm lamb twins were all given surfactant before the first breath. One lamb in each pair was randomised to receive large lung inflations immediately after surfactant while the other twin underwent similar inflations at 10-15 min of age. SETTING: Animal laboratory. EXPERIMENTAL ANIMALS: Anaesthetized lambs delivered by cesarean section at a gestational age of 127 days. INTERVENTIONS: Surfactant supplementation at birth. Five sustained lung inflations of 16 ml/kg at different times in relation to surfactant instillation. Pressure-limited mechanical ventilation for 4 h. MEASUREMENTS AND RESULTS: The response to surfactant was assessed by ventilator settings, lung mechanics and lung histology. Preceding surfactant supplementation did not prevent the adverse effect of large lung inflations at birth on ventilatory efficiency and lung mechanics, but seemed to protect against severe lung injury. No adverse effect was seen from large lung inflations given at 10 min of age or later. CONCLUSION: Prophylactic surfactant supplementation does not fully protect against the harmful effect of large lung inflations during a short sensitive period immediately after birth.

Age Factors↗

PubMed2003

A synthetic surfactant based on a poly-Leu SP-C analog and phospholipids: effects on tidal volumes and lung gas volumes in ventilated immature newborn rabbits.

Available surfactants for treatment of respiratory distress syndrome in newborn infants are derived from animal lungs, which limits supply and poses a danger of propagating infectious material. Poly-Val-->poly-Leu analogs of surfactant protein (SP)-C can be synthesized in large quantities and exhibit surface activity similar to SP-C. Here, activity of synthetic surfactants containing a poly-Leu SP-C analog (SP-C33) was evaluated in ventilated premature newborn rabbits. Treatment with 2.5 ml/kg body wt of 2% (wt/wt) SP-C33 in 1,2-dipalmitoyl-sn-3-glycero phosphoryl choline (DPPC)-1-palmitoyl-2-oleoyl-sn-3-glycero phosphoryl choline (POPC)-1-palmitoyl-2-oleoyl-sn-3-glycero phosphoryl glycerol (POPG), 68:0:31, 68:11:20, or 68:16:15 (wt/wt/wt) suspended at 80 mg/ml gave tidal volumes (Vt) of 20-25 ml/kg body wt, with an insufflation pressure of 25 cmH2O and no positive end-expiratory pressure (PEEP), comparable to the Vt for animals treated with the porcine surfactant Curosurf. Nontreated littermates had a Vt of approximately 2 ml/kg body wt. The Vt for SP-C33 in DPPC-egg phosphatidylglycerol-palmitic acid [68:22:9 (wt/wt/wt)], DPPC-POPG-palmitic acid [68:22:9 (wt/wt/wt)], and DPPC-POPC-POPG [6:2:2 (wt/wt/wt)] was 15-20 ml/kg body wt. Histological examination of lungs from animals treated with SP-C33-based surfactants showed incomplete, usually patchy air expansion of alveolar spaces associated with only mild airway epithelial damage. Lung gas volume after 30 min of mechanical ventilation were more than threefold larger in animals treated with Curosurf than in those receiving SP-C33 in DPPC-POPC-POPG, 68:11:20. This difference could be largely counterbalanced by ventilation with PEEP (3-4 cmH2O). An artificial surfactant based on SP-C33 improves Vt in immature newborn animals ventilated with standardized peak pressure but requires PEEP to build up adequate lung gas volumes.

Amino Acid Sequence↗

PubMed2003

Modified protocols for surfactant therapy in experimental meconium aspiration syndrome.

In adult rats with experimental meconium aspiration syndrome, we investigated whether the therapeutic effect of exogenous surfactant was increased by addition of dextran or preceding airway lavage with diluted surfactant. Animals (n = 72) ventilated with pure oxygen were given human meconium suspension (50-75 mg kg(-1)) through the airways. When the PaO(2) had decreased to <20 kPa (mean +/- SD 12 +/- 3.9 kPa), the rats were randomly allocated to ten groups (G). G 6-10 underwent lung lavage with diluted Curosurf (5 mg ml(-1), 20 ml kg(-1)), whereas G 1-5 did not. G 1 and 6 received no additional material through the airways. G 2 and 7 received Curosurf (100 mg kg(-1)), and G 3 and 8 received Curosurf (100 mg kg(-1)) plus dextran (75 mg kg(-1)); G 4 and 9 received Curosurf (200 mg kg(-1)), and G 5 and G 10 received Curosurf (200 mg kg(-1)) plus dextran (75 mg kg(-1)). All rats in G 1 died before 180 min after randomization. In G 2, 3, 6, 7, and 8, the PaO(2) transiently increased to 30-40 kPa. In G 4, 5, 9, and 10, the PaO(2) remained >30 kPa for 180 min. Both airway lavage and supplementation with dextran improved the therapeutic effects of surfactant; however, a large dose (200 mg kg(-1)) was nevertheless required to optimize gas exchange.

Animals↗