An Amphipathic α-Helical Decapeptide in Phosphatidylcholine Is an Effective Synthetic Lung Surfactant

McLean, Larry R.; Lewis, Jon; Krstenansky, John L.; Hagaman, Karen A.; Cope, Angela S.; Olsen, Karl; Matthews, Emily R.; Uhrhammer, Dennis C.; Owen, Thomas J.; Payne, Marguerite H.

doi:10.1164/ajrccm/147.2.462

Cited by 29 publications

(14 citation statements)

References 16 publications

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“…Admixtures of DPPC and variable proportions of these simple peptides had enough surface activity to mimic pulmonary surfactant in animal models of surfactant deficiency [89][90][91][92]. This evidence provides support for the idea that a clinical surfactant could, in principle, be produced by a proper combination of lipids and synthetic peptides.…”

supporting

confidence: 52%

Synthetic Pulmonary Surfactant Preparations: New Developments and Future Trends

Mingarro¹,

Lukovic²,

Vilar³

et al. 2008

CMC

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Pulmonary surfactant is a lipid-protein complex that coats the interior of the alveoli and enables the lungs to function properly. Upon its synthesis, lung surfactant adsorbs at the interface between the air and the hypophase, a capillary aqueous layer covering the alveoli. By lowering and modulating surface tension during breathing, lung surfactant reduces respiratory work of expansion, and stabilises alveoli against collapse during expiration.Pulmonary surfactant deficiency, or dysfunction, contributes to several respiratory pathologies, such as infant respiratory distress syndrome (IRDS) in premature neonates, and acute respiratory distress syndrome (ARDS) in children and adults. The main clinical exogenous surfactants currently in use to treat some of these pathologies are essentially organic extracts obtained from animal lungs. Although very efficient, natural surfactants bear serious defects: i) they could vary in composition from batch to batch; ii) their production involves relatively high costs, and sources are limited; and iii) they carry a potential risk of transmission of animal infectious agents and the possibility of immunological reaction. All these caveats justify the necessity for a highly controlled synthetic material.In the present review the efforts aimed at new surfactant development, including the modification of existing exogenous surfactants by adding molecules that can enhance their activity, and the progress achieved in the production of completely new preparations, are discussed. Pulmonary surfactant function and dysfunctionThe respiratory surface of lungs constitutes the largest area of the human body exposed to the environment. Efficient gas exchange requires a large enough surface to be continuously exposed to air while minimising the barriers for oxygen and carbon dioxide to diffuse between air and the blood compartment [1]. At the same time, a selection of combined defence mechanisms is required to help keep such an essentially exposed area sterile of potential pathogenic microorganisms. Pulmonary surfactant, a lipid-protein complex produced by the alveolar epithelium of lungs, has been optimised to coordinate two main activities through natural evolution. On the one hand, it stabilises the respiratory surface against physical forces, therefore minimising the work required to maintain the large respiratory surface open to air [2][3][4]. On the other hand, pulmonary surfactant contains elements responsible for establishing a primary innate antipathogenic barrier, essential to ensure an intrinsically low pathogen load in the absence of induced defence mechanisms [5]. Extensive research in the last few decades has revealed some of the molecular mechanisms involved in pulmonary surfactant action. However, the manner in which both the biophysical and defence activities are intermingled and coordinately modulated in the alveolar spaces is now only beginning to be envisioned.Pulmonary surfactant is composed of approximately 90% lipids and 8-10% proteins, although only around 5% ...

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supporting

confidence: 52%

Synthetic Pulmonary Surfactant Preparations: New Developments and Future Trends

Mingarro¹,

Lukovic²,

Vilar³

et al. 2008

CMC

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“…Several studies on synthetic peptides that exhibit surfactant activity in vitro have been reported (e.g. Baatz et al, 1991;Vincent et al, 1991;McLean et al, 1993;Johansson et al, 1995a;Lipp et al, 1996). It is however difficult to judge the pharmacological impact from such studies alone, since simple homopolymeric peptides also exhibit similar effects (Venkitaraman et al, 1990), and apparently few of these peptides possess significant effects in vivo.…”

Section: Structures Interactions and Dynamics In Relation To Functiomentioning

confidence: 99%

Molecular Structures and Interactions of Pulmonary Surfactant Components

Johansson

Curstedt

1997

European Journal of Biochemistry

272

217

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The dominating functional property of pulmonary surfactant is to reduce the surface tension at the alveolar aidliquid 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 collagenousAectin hybrid properties and functionally are Caz+-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 a-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.

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“…Also, synthetic peptides with simplified sequences designed to mimic specific parts of the SP-B polypeptide [258,260], and amphipathic α-helical peptides based on SP-A [261], exhibit some surface activity in combination with phospholipids. However, although encouraging, such results should perhaps be taken somewhat cautiously, since an amphipathic α-helical decapeptide with a sequence unrelated to SP-B [262], or simple amino acid homopolymers [263] combined with phospholipids also exhibit biophysical activities that are superior to phospholipids alone, but inferior to natural pulmonary surfactant.…”

Section: Functional Correlationsmentioning

confidence: 99%

The proteins of the surfactant system

Johansson¹,

Curstedt²,

Robertson³

1994

Eur Respir J

203

143

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T Th he e p pr ro ot te ei in ns s o of f t th he e s su ur rf fa ac ct ta an nt t s sy ys st te em m SP-B is a 79-residue polypeptide that contains three intrachain disulphide bridges. It exists mainly as a homodimer, which is strongly positively charged and may selectively remove anionic and unsaturated lipid species from the alveolar surface film, thereby increasing surface pressure.SP-C is a mainly α-helical, extraordinarily hydrophobic polypeptide containing 35 amino acid residues and covalently linked palmitoyl groups. Its α-helical portion is inserted into surfactant lipid bilayers. SP-C accelerates the adsorption of lipid bilayers to an interfacial monolayer. In babies with respiratory distress syndrome, the clinical response to treatment with surfactant containing SP-B and SP-C is much faster than in babies treated with protein-free synthetic surfactant.We speculate that, in the near future, surfactant preparations based on recombinant hydrophobic proteins will be available for clinical use.

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An Amphipathic α-Helical Decapeptide in Phosphatidylcholine Is an Effective Synthetic Lung Surfactant

Cited by 29 publications

References 16 publications

Synthetic Pulmonary Surfactant Preparations: New Developments and Future Trends

Synthetic Pulmonary Surfactant Preparations: New Developments and Future Trends

Molecular Structures and Interactions of Pulmonary Surfactant Components

The proteins of the surfactant system

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