Synthetic Surfactant Protein Analogues

Johansson, Jan; Gustafsson, Magnus; Palmblad, Marie; Zaltash, Shahparak; Robertson, Bengt; Curstedt, Tore

doi:10.1159/000047029

Cited by 23 publications

(17 citation statements)

References 27 publications

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“…Among the surfactant apoproteins, SP-B is known to be particularly active in improving the adsorption and film behavior of lipids [1], [39]–[47]. The Mini-B used here was designed to maintain several important structural features of full-length human SP-B [25].…”

Section: Discussionmentioning

confidence: 99%

Dynamic Surface Activity of a Fully Synthetic Phospholipase-Resistant Lipid/Peptide Lung Surfactant

et al. 2007

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BackgroundThis study examines the surface activity and resistance to phospholipase degradation of a fully-synthetic lung surfactant containing a novel diether phosphonolipid (DEPN-8) plus a 34 amino acid peptide (Mini-B) related to native surfactant protein (SP)-B. Activity studies used adsorption, pulsating bubble, and captive bubble methods to assess a range of surface behaviors, supplemented by molecular studies using Fourier transform infrared (FTIR) spectroscopy, circular dichroism (CD), and plasmon resonance. Calf lung surfactant extract (CLSE) was used as a positive control.ResultsDEPN-8+1.5% (by wt.) Mini-B was fully resistant to degradation by phospholipase A2 (PLA2) in vitro, while CLSE was severely degraded by this enzyme. Mini-B interacted with DEPN-8 at the molecular level based on FTIR spectroscopy, and had significant plasmon resonance binding affinity for DEPN-8. DEPN-8+1.5% Mini-B had greatly increased adsorption compared to DEPN-8 alone, but did not fully equal the very high adsorption of CLSE. In pulsating bubble studies at a low phospholipid concentration of 0.5 mg/ml, DEPN-8+1.5% Mini-B and CLSE both reached minimum surface tensions <1 mN/m after 10 min of cycling. DEPN-8 (2.5 mg/ml)+1.5% Mini-B and CLSE (2.5 mg/ml) also reached minimum surface tensions <1 mN/m at 10 min of pulsation in the presence of serum albumin (3 mg/ml) on the pulsating bubble. In captive bubble studies, DEPN-8+1.5% Mini-B and CLSE both generated minimum surface tensions <1 mN/m on 10 successive cycles of compression/expansion at quasi-static and dynamic rates.ConclusionsThese results show that DEPN-8 and 1.5% Mini-B form an interactive binary molecular mixture with very high surface activity and the ability to resist degradation by phospholipases in inflammatory lung injury. These characteristics are promising for the development of related fully-synthetic lipid/peptide exogenous surfactants for treating diseases of surfactant deficiency or dysfunction.

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Section: Discussionmentioning

confidence: 99%

Dynamic Surface Activity of a Fully Synthetic Phospholipase-Resistant Lipid/Peptide Lung Surfactant

et al. 2007

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“…Although both of the hydrophobic lung surfactant proteins are known to enhance phospholipid activity, multiple studies indicate that SP-B is more effective than SP-C on a weight and molar basis (13,25,34,40,41,44,46,48,56,58). SP-B has been shown to be more active than SP-C in increasing both the adsorption and dynamic surface tension lowering of phospholipids (13,44,46,48,56,58).…”

Section: Discussionmentioning

confidence: 99%

“…The hydrophobic surfactant proteins SP-B and SP-C both have strong molecular interactions with lipids. Because of its combination of polar and nonpolar residues and overall amphipathic structure, SP-B can interact with both phospholipid head groups and fatty chains and is particularly active in enhancing surface active behavior in endogenous and exogenous lung surfactants (13,25,34,44,46,48,56,58). However, the content-dependent effects of SP-B on the surface and physiological activity of lipids have not been fully quantitated.…”

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confidence: 99%

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

Wang

Baatz

Holm

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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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.

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“…However, fully synthetic lung surfactants ultimately will need to incorporate peptide components that are manufactured in vitro. Significant research effort has been directed at designing and synthesizing amphipathic peptides for use in exogenous lung surfactants, but replacing highly active native SP-B/C with synthetic substitutes has proven to be challenging (2,51). The results of the present study indicate that fully synthetic surfactants of extremely high activity could be formulated by combining DEPN-8 with one or more synthetic peptides related to SP-B/C.…”

Section: Table 2 Calculated Percent Volume Recoveries At Low Transpumentioning

confidence: 85%

Activity and Inhibition Resistance of a Phospholipase-Resistant Synthetic Surfactant in Rat Lungs

Wang¹,

Chang²,

Schwan³

et al. 2007

Am J Respir Cell Mol Biol

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This study investigates the activity and inhibition resistance in excised rat lungs of a novel synthetic surfactant containing the phospholipase-resistant diether phosphonolipid DEPN-8 plus 1.5% bovine surfactant protein (SP)-B/C compared to calf lung surfactant extract (CLSE). DEPN-8 1 1.5% SP-B/C surpassed CLSE in normalizing surfactant-deficient pressure-volume (P-V) deflation mechanics in lavaged excised lungs in the presence of phospholipase A 2 (PLA 2 ) or C18:1 lyso-phosphatidylcholine (LPC). DEPN-8 1 1.5% SP-B/C had activity equal to CLSE in normalizing P-V mechanics in the absence of inhibitors or in the presence of serum albumin. These physiologic activity findings were directly consistent with surface activity measurements on the pulsating bubble surfactometer. In the absence of inhibitors, DEPN-8 1 1.5% SP-B/C and CLSE rapidly reached minimum surface tensions , 1 mN/m (0.5 and 2.5 mg surfactant phospholipid/ ml). DEPN-8 1 1.5% SP-B/C maintained its high surface activity in the presence of PLA 2 , while the surface activity of CLSE was significantly inhibited by exposure to this enzyme. DEPN-8 1 1.5% SP-B/C also had greater surface activity than CLSE in the presence of LPC, and the two surfactants had equivalent surface activity in the presence of albumin. DEPN-8 1 1.5% SP-B/C also had slightly greater surface activity than CLSE when exposed to peroxynitrite in pulsating bubble studies. These results support the potential of developing highly active and inhibition-resistant synthetic exogenous surfactants containing DEPN-8 1 apoprotein/peptide constituents for use in treating direct pulmonary forms of clinical acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS).

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Synthetic Surfactant Protein Analogues

Cited by 23 publications

References 27 publications

Dynamic Surface Activity of a Fully Synthetic Phospholipase-Resistant Lipid/Peptide Lung Surfactant

Dynamic Surface Activity of a Fully Synthetic Phospholipase-Resistant Lipid/Peptide Lung Surfactant

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

Activity and Inhibition Resistance of a Phospholipase-Resistant Synthetic Surfactant in Rat Lungs

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