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

Walther, Frans J.; Waring, Alan J.; Hernández-Juviel, José M.; Gordon, Larry M.; Schwan, Adrian L.; Jung, Chun‐Ling; Chang, Yusuo; Wang, Zhengdong; Notter, Robert H.

doi:10.1371/journal.pone.0001039

Cited by 29 publications

(38 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, several synthetic exogenous surfactants are under clinical study and laboratory research. [16][17][18][19][20][21][22][23][24] …”

Section: A Brief Historymentioning

confidence: 99%

“…One particularly active synthetic lipid analog of this kind is DEPN-8, a phospholipase-resistant diether lipid developed by Notter and co-workers. 19,21,23,46,47 Synthetic surfactants containing DEPN-8 or other phospholipase-resistant lipids plus active SP-B peptides have the potential for particular utility in ALI/ ARDS, 19,21,23,[48][49][50] where these lytic enzymes can be elaborated in high concentrations during the inflammatory response in injured lungs. [51][52][53][54][55][56][57] Regardless of category (animal-derived or synthetic), the requirements for an effective therapeutic surfactant in ALI/ARDS are more stringent than is the case for RDS.…”

Section: Pharmaceutical Surfactantsmentioning

confidence: 99%

See 1 more Smart Citation

The Future of Exogenous Surfactant Therapy

Willson

Notter

2011

Respir Care

View full text Add to dashboard Cite

Since the identification of surfactant deficiency as the putative cause of the infant respiratory distress syndrome (RDS) by Avery and Mead in 1959, our understanding of the role of pulmonary surfactant in respiratory physiology and the pathophysiology of acute lung injury (ALI) has advanced substantially. Surfactant replacement has become routine for the prevention and treatment of infant RDS and other causes of neonatal lung injury. The role of surfactant in lung injury beyond the neonatal period, however, has proven more complex. Relative surfactant deficiency, dysfunction, and inhibition all contribute to the disturbed physiology seen in ALI and acute respiratory distress syndrome (ARDS). Consequently, exogenous surfactant, while a plausible therapy, has proven to be less effective in ALI/ ARDS than in RDS, where simple deficiency is causative. This failure may relate to a number of factors, among them inadequacy of pharmaceutical surfactants, insufficient dosing or drug delivery, poor drug distribution, or simply an inability of the drug to substantially impact the underlying pathophysiology of ALI/ARDS. Both animal and human studies suggest that direct types of ALI (eg, aspiration, pneumonia) may be more responsive to surfactant therapy than indirect lung injury (eg, sepsis, pancreatitis). Animal studies are needed, however, to further clarify aspects of drug composition, timing, delivery, and dosing before additional human trials are pursued, as the results of human trials to date have been inconsistent and largely disappointing. Further study and perhaps the development of more robust pharmaceutical surfactants offer promise that exogenous surfactant will find a place in our armamentarium of treatment of ALI/ARDS in the future. Key words: surfactant; infant respiratory distress syndrome; RDS; acute lung injury; ALI; acute respiratory distress syndrome; ARDS; neonatal. [Respir Care 2011;56(9):1369 -1386.

show abstract

“…In addition, several synthetic exogenous surfactants are under clinical study and laboratory research. [16][17][18][19][20][21][22][23][24] …”

Section: A Brief Historymentioning

confidence: 99%

Section: Pharmaceutical Surfactantsmentioning

confidence: 99%

The Future of Exogenous Surfactant Therapy

Willson

Notter

2011

Respir Care

View full text Add to dashboard Cite

show abstract

“…Phospholipase-induced degradation of lung surfactant glycerophospholipids not only reduces the concentration of active components, but also generates reaction products such as lysophosphatidylcholine and fluid free fatty acids that can further decrease surface activity by interacting biophysically with remaining surfactant at the alveolar interface [55,59,70]. Synthetic exogenous surfactants containing such phosphonolipids combined with purified surfactant proteins or synthetic peptides have very high overall surface activity plus an ability to resist phospholipases in ALI/ARDS [71,[208][209][210][211]219]. On-going basic research is continuing to design and synthesize peptides related to SP-B and other surfactant proteins for use in highly-active fully-synthetic exogenous surfactants in combination with either normal glycerophospholipids or phospholipase-resistant analogs.…”

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Based on the anti-inflammatory effects of HA and its ability to reduce PLA 2 activity, and thus minimize surfactant inhibition, it has been suggested that concomitant treatment with HA and surfactant might provide a promising approach to the treatment of ARDS. An alternative approach, described in recent papers, has focused on the use of PLA 2 -resistant surface-active phosphonolipids to develop new artificial surfactants (49,66,67), which may eventually prove to have advantages in the treatment of ARDS.…”

Section: Discussionmentioning

confidence: 99%

An albumin-associated PLA₂-like activity inactivates surfactant phosphatidylcholine secreted from fetal type II pneumocytes

Cake

2011

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Damas JE, Cake MH. An albumin-associated PLA2-like activity inactivates surfactant phosphatidylcholine secreted from fetal type II pneumocytes. Am J Physiol Lung Cell Mol Physiol 301: L966-L974, 2011. First published September 9, 2011 doi:10.1152/ajplung.00103.2011.-Type II pneumocytes are responsible for the synthesis and secretion of pulmonary surfactant, which reduces surface tension in lung alveoli, thus decreasing their tendency to collapse during expiration. For this effect to be sustained, the integrity of the surface-active components of surfactant must be maintained. This study has shown that, when cultured type II pneumocytes are exposed to lipoprotein-free serum (LFS), the level of lyso-phosphatidylcholine (lyso-PC) in the secreted surfactant phospholipids is markedly elevated with a concomitant decline in the level of phosphatidylcholine (PC). This effect is the result of hydrolysis of surfactant PC by a phospholipase A2 (PLA2)-like activity present within serum. Anion-exchange chromatography, gel filtration chromatography and preparative electrophoresis of human LFS have shown that this PLA2-like activity coelutes with albumin and is biochemically distinct from the secretory form of PLA2. Furthermore, specific inhibitors of PLA2 such as pbromophenacyl bromide, aristolochic acid, and palmitoyl trifluoromethyl ketone do not inhibit this activity of serum. Commercially purified human serum albumin fraction V and recombinant human serum albumin (rHSA) are almost as effective as LFS in enhancing the level of lyso-PC in the media. The latter finding implies that rHSA directly generates lyso-PC from secreted PC and suggests that this PLA2-like activity may be an intrinsic attribute of albumin. surfactant phospholipids; phosphatidylcholine deacylation; lyso-phosphatidylcholine PULMONARY SURFACTANT IS ESSENTIAL for normal lung function. Through its ability to adsorb rapidly to the alveolar surface and reduce surface tension, surfactant increases lung compliance, thereby reducing the work of breathing (19,50,52). The ability of surfactant films to attain very low surface tension during compression stabilizes lung alveoli at end expiration by preventing alveolar collapse. The essential role of pulmonary surfactant in normal lung function is illustrated by the proven efficacy of exogenous surfactant to act as a replacement in the treatment of neonatal respiratory distress syndrome (NRDS) (8,20,33,62). Acute respiratory distress syndrome (ARDS), which can affect both adults and children, has a more complicated pathology than the simple absence of surfactant but shares many of the symptoms of NRDS, such as diminished lung compliance, a marked reduction in effective lung volume and profound hypoxemia (23). However, clinical trials with the most effective formulations of synthetic surfactant, which had been used successfully in the treatment of NRDS, showed that these formulations had only a modest and transient beneficial effect when administered to ARDS patients (45). Extracted bronchial fluid (lavage) from ARDS...

show abstract

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

Cited by 29 publications

References 60 publications

The Future of Exogenous Surfactant Therapy

The Future of Exogenous Surfactant Therapy

Surfactant for Pediatric Acute Lung Injury

An albumin-associated PLA₂-like activity inactivates surfactant phosphatidylcholine secreted from fetal type II pneumocytes

Contact Info

Product

Resources

About