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

Wang, Z.; Baatz, John E.; Holm, Bruce A.; Notter, Robert H.

doi:10.1152/ajplung.00431.2001

Cited by 24 publications

(21 citation statements)

References 55 publications

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“…Survanta has an SP-B content by ELISA of only 0.044% by weight relative to phospholipid, while CLSE (Infasurf®) has an SP-B content of 0.9% by weight that approaches that of lavaged whole surfactant [118]. SP-B is known to be the most active of the hydrophobic surfactant proteins in enhancing the adsorption, dynamic surface activity, and inhibition resistance of phospholipids [118,[176][177][178][179][180][181][182][183][184]. The addition of bovine SP-B or synthetic SP-B peptides to Survanta® significantly improves its surface and physiological activity towards that of Infasurf and whole surfactant [106,118,175] (Figure 5)‥ Despite its lack of SP-B, other active components such as SP-C in Survanta® allow it to have significant efficacy in some forms of ALI/ARDS as noted earlier (e.g., [130,131,133]).…”

Section: Activity and Inhibition Resistance Of Exogenous Surfactant Dmentioning

confidence: 99%

“…However, the 21 amino acid KL4 peptide is only a very rough structural analog to native SP-B, and advances in peptide molecular modeling and synthesis technology support the feasibility of preparing new SP-B peptides with significantly greater sequence and molecular folding specificity, and correspondingly higher activity ( [202][203][204] for review). The development of new synthetic SP-B peptides is particularly important for optimal synthetic exogenous surfactants given the greater activity of SP-B compared to SP-C in native surfactant noted earlier [118,[176][177][178][179][180][181][182][183][184]. In addition to peptide/protein components in new synthetic surfactants, it is also important to consider their lipid constituents.…”

Section: Examples Of Research On New Synthetic Exogenous Surfactamentioning

confidence: 99%

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Surfactant for Pediatric Acute Lung Injury

Willson¹,

Chess²,

Notter³

2008

Pediatric Clinics of North America

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SynopsisThis article reviews exogenous surfactant therapy and its use in mitigating acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) in infants, children, and adults. Biophysical and animal research documenting surfactant dysfunction in ALI/ARDS is described, and the scientific rationale for treatment with exogenous surfactant is discussed. Major emphasis is on reviewing clinical studies of surfactant therapy in pediatric and adult patients with ALI/ARDS. Particular advantages from surfactant therapy in direct pulmonary forms of these syndromes are described. Also discussed are additional factors affecting the efficacy of exogenous surfactants in ALI/ARDS, including the multifaceted pathology of inflammatory lung injury, the effectiveness of surfactant delivery in injured lungs, and composition-based activity differences among clinical exogenous surfactant preparations.

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Section: Activity and Inhibition Resistance Of Exogenous Surfactant Dmentioning

confidence: 99%

Section: Examples Of Research On New Synthetic Exogenous Surfactamentioning

confidence: 99%

Surfactant for Pediatric Acute Lung Injury

Willson¹,

Chess²,

Notter³

2008

Pediatric Clinics of North America

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“…In vitro, surfactant phospholipids in the absence of surfactant proteins have a slow adsorption rate to the surface film and do not achieve low surface tensions; normal surfactant properties are restored in a dose-dependent fashion by reconstitution of lipids with SP-B, with a nearly optimal response at 0.75% SP-B/phospholipid (12,13). In animal studies, absence of SP-B by gene ablation or neutralization of SP-B with antibodies causes respiratory distress (8 -10).…”

mentioning

confidence: 99%

Dysfunction of Pulmonary Surfactant in Chronically Ventilated Premature Infants

Merrill¹,

Ballard²,

Cnaan³

et al. 2004

Pediatr Res

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Infants of Ͻ30 wk gestation often require respiratory support for several weeks and may develop bronchopulmonary dysplasia (BPD), which is associated with long-term pulmonary disability or death in severe cases. To examine the status of surfactant in infants at high risk for BPD, this prospective study analyzed 247 tracheal aspirate samples from 68 infants of 23-30 wk gestation who remained intubated for 7-84 d. Seventy-five percent of the infants had one or more surfactant samples with abnormal function (minimum surface tension 5.1-21.7 mN/m by pulsating bubble surfactometer), which were temporally associated with episodes of infection (p ϭ 0.01) and respiratory deterioration (p ϭ 0.005). Comparing normal and abnormal surfactant samples, there were no differences in amount of surfactant phospholipid, normalized to total protein that was recovered from tracheal aspirate, or in relative content of phosphatidylcholine and phosphatidylglycerol. Contents of surfactant proteins (SP) A, B, and C, measured in the surfactant pellet by immunoassay, were reduced by 50%, 80%, and 72%, respectively, in samples with abnormal surface tension (p Յ 0.001). On multivariable analysis of all samples, SP-B content (r ϭ Ϫ0.58, p Ͻ 0.0001) and SP-C content (r ϭ Ϫ0.32, p Ͻ 0.001) were correlated with surfactant function. We conclude that most premature infants requiring continued respiratory support after 7 d of age experience transient episodes of dysfunctional surfactant that are associated with a deficiency of SP-B and SP-C. Infants born prematurely, particularly those of Յ30 wk gestation, are at high risk for lung disease. Although the incidence and severity of respiratory distress syndrome has been reduced with antenatal corticosteroid therapy, which hastens lung development, and postnatal replacement surfactant treatment, newborn respiratory distress remains a frequent occurrence in very low birth weight infants and a requirement for respiratory support often continues for many weeks (1, 2). The clinical pattern after the first week of life frequently includes episodes of respiratory deterioration necessitating increased inspired oxygen or ventilatory support (3). In some infants, lung disease progresses to BPD, which is defined as a continuing requirement for supplemental oxygen and/or positive pressure ventilatory support at 36 wk postmenstrual age (4). BPD occurs in approximately 30% of infants with birth weights Ͻ1000 g and is associated with long-term pulmonary and/or neurodevelopmental disability or death in severe cases (4, 5). The etiology of this progressive respiratory insufficiency is likely multifactorial, including oxygen toxicity, volutrauma associated with mechanical ventilation, infection, patent ductus arteriosus, and inflammation, and results in arrest of alveolar development and interstitial fibrosis (4).Pulmonary surfactant is a mixture of lipids and proteins produced by alveolar type II cells. The major phospholipid component, saturated phosphatidylcholine, forms a highly surface-active film in lung alveoli ...

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“…S1D), the values of K i were calculated to be 2.3 μM for SP-B1-25-X1 and 1.6 μM for SP-B1-25-X2. A check of the constraint [E] o /K i < 0.1, (8) Values are the mean ± SD (number of animals in parentheses). The red blood cell pellet was obtained by saline bronchoalveolar lavage of the lungs 2 h after treatment followed by centrifugation.…”

Section: X2mentioning

confidence: 99%

“…Although pulmonary surfactant is a complex mixture of lipids and peptides, SP-B is the clear choice as a covalent partner for an HNE inhibitor because <1% by weight mixed with lipids dramatically enhances adsorption, reduces surface tension, and restores normal pressure-volume mechanics in rat lungs depleted of surfactant (8). The N-terminal 1-25 (SP-B1-25) peptide fragment can be used because its surface-active properties are comparable to the whole SP-B 79-mer (9,10).…”

mentioning

confidence: 99%

A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema

Guarnieri

Spencer²,

Lucey³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Two million Americans suffer from pulmonary emphysema, costing $2.5 billion/year and contributing to 100,000 deaths/year. Emphysema is thought to result from an imbalance between elastase and endogenous inhibitors of elastase, leading to tissue destruction and a loss of alveoli. Decades of research have still not resulted in an effective treatment other than stopping cigarette smoking, a highly addictive behavior. On the basis of our previous work, we hypothesize that small molecule inhibitors of human neutrophil elastase are ineffective because of rapid clearance from the lungs. To develop a long-acting elastase inhibitor with a lung pharmacodynamic profile that has minimal immunogenicity, we covalently linked an elastase inhibitor, similar to a trifluoro inhibitor that was used in clinical trials, to a 25-amino-acid fragment of human surfactant peptide B. We used this construct to prevent human neutrophil elastaseinduced emphysema in a rodent model. The elastase inhibitor alone, although in a 70-fold molar excess to elastase in a mixture with <0.6% residual elastase activity, provided no protection from elastase-induced emphysema. Covalently combining an endogenous peptide from the target organ with a synthetic small molecule inhibitor is a unique way of endowing an active compound with the pharmacodynamic profile needed to create in vivo efficacy.lung cancer | resistant infections | tuberculosis | asthma I nhalation is an important means of systemically delivering drugs that require immediate onset of action because the lungs provide a facile conduit to the bloodstream (1). Conversely, rapid lung clearance of small molecules causes a significant challenge for the development of pulmonary therapeutics. Rodent models of elastase-induced emphysema, for example, highlight the challenges for the development of effective drugs for pulmonary diseases. Potent in vitro human neutrophil elastase (HNE) inhibitors are cleared from the animals' lungs in minutes and may even exacerbate HNEinduced emphysema (2), whereas one intratracheally instilled dose of elastase causes maximum lung damage after 4 wk (3). The combination of long-term chronic pulmonary damage that characterizes the progression of emphysema with the rapid lung clearance (4) and potential nephrotoxicity (5) of small molecule drugs indicates that there is a profound need for new ways of producing pulmonary therapeutics with long lung residence time pharmacodynamics.Because emphysema is a chronic disease, any treatment will likely be administered over the course of the patient's life, and thus long-acting agents may induce an immune response that would negate the therapeutic effect. The ability of the treatment to access all regions of the vast lung surface area must also be considered. One way to slow the clearance of a small molecule inhibitor from the lung is to attach it to a larger polymer (6). For instance, the covalent linkage of a hydrophilic polymer to a peptidyl carbamate inhibitor increases the half-life by 100-fold in the lungs of hamsters and pro...

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

Cited by 24 publications

References 55 publications

Surfactant for Pediatric Acute Lung Injury

Surfactant for Pediatric Acute Lung Injury

Dysfunction of Pulmonary Surfactant in Chronically Ventilated Premature Infants

A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema

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