Chemical synthesis and surface activity of lung surfactant phospholipid analogs. II. Racemic N-substituted diether phospholipids

Turcotte, Joseph G.; Lin, Winnie H.; Pivarnik, Philip E.; Sacco, A.M.; Shirali, Shyam; Bermel, Marc M.; Lu, Zhong E; Notter, Robert H.

doi:10.1016/0005-2760(91)90048-m

Cited by 24 publications

(36 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2 and 3; Table 1). DEPN-8 also has ether, rather than ester, linkages between the fatty chains and the glycerol backbone, plus a methylene for oxygen substitution in the head group so that it is a phosphonolipid rather than a phospholipid (30,51,52). Ether linkages in DEPN-8 increase chain mobility and facilitate film respreading during cycling (31,32,52).…”

Section: Discussionmentioning

confidence: 99%

“…The diether phosphonolipid DEPN-8 was synthesized by a modification of the methods of Turcotte et al (51,52). The following reaction intermediates and synthesis/purification protocols were used.…”

Section: Synthesis and Purification Of Depn-8mentioning

confidence: 99%

“…Concentration of lipid-containing fractions was followed by partial drying by the addition and removal of benzene (6ϫ 60 ml) on the rotary evaporator to give 2.11 g of damp lipid. This material was dried to constant weight under vacuum at 50°C in a rotating tube oven in the presence of P2O5 to afford 1.89 g (yield 55% over two steps) of pure DEPN-8, melting point 208°C decomposition; literature 195°C decomposition (51).…”

Section: Synthesis and Purification Of Depn-8mentioning

confidence: 99%

“…The present study investigates a synthetic phospholipase-resistant C16:0 diether phosphonolipid analog of DPPC (designated DEPN-8) originally synthesized by Turcotte, Notter, and coworkers (51,52). DEPN-8 is studied both as a pure compound and in combination with column-purified mixed hydrophobic surfactant proteins (SP)-B and SP-C from calf lung surfactant extract (CLSE).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Surface activity of a synthetic lung surfactant containing a phospholipase-resistant phosphonolipid analog of dipalmitoyl phosphatidylcholine

Wang¹,

Schwan²,

Lairson³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Surface activity of a synthetic lung surfactant containing a phospholipase-resistant phosphonolipid analog of dipalmitoyl phosphatidylcholine. Am J Physiol Lung Cell Mol Physiol 285: L550-L559, 2003; 10.1152/ajplung.00346.2002.-Surface activity and sensitivity to inhibition from phospholipase A2 (PLA2), lysophosphatidylcholine (LPC), and serum albumin were studied for a synthetic C16:0 diether phosphonolipid (DEPN-8) combined with 1.5% by weight of mixed hydrophobic surfactant proteins (SP)-B/C purified from calf lung surfactant extract (CLSE). Pure DEPN-8 had better adsorption and film respreading than the major lung surfactant phospholipid dipalmitoyl phosphatidylcholine and reached minimum surface tensions Ͻ1 mN/m under dynamic compression on the Wilhelmy balance and on a pulsating bubble surfactometer (37°C, 20 cycles/min, 50% area compression). DEPN-8 ϩ 1.5% SP-B/C exhibited even greater adsorption and had overall dynamic surface tension lowering equal to CLSE on the bubble. In addition, films of DEPN-8 ϩ 1.5% SP-B/C on the Wilhelmy balance had better respreading than CLSE after seven (but not two) cycles of compression-expansion at 23°C. DEPN-8 is structurally resistant to degradation by PLA2, and DEPN-8 ϩ 1.5% SP-B/C maintained high adsorption and dynamic surface activity in the presence of this enzyme. Incubation of CLSE with PLA2 led to chemical degradation, generation of LPC, and reduced surface activity. DEPN-8 ϩ 1.5% SP-B/C was also more resistant than CLSE to direct biophysical inhibition by LPC, and the two were similar in their sensitivity to biophysical inhibition by serum albumin. These findings indicate that synthetic surfactants containing DEPN-8 combined with surfactant proteins or related synthetic peptides have potential utility for treating surfactant dysfunction in inflammatory lung injury. exogenous surfactants; phospholipid analogs; phospholipase A2; phospholipase resistance; inhibition resistance; diether phosphonolipid; surfactant proteins ENDOGENOUS LUNG SURFACTANT contains functionally important lipids and apoproteins (37), and its activity is compromised when these essential components are chemically degraded or altered. One important cause of such effects is through the action of phospholipases or proteases during inflammatory lung injury. Lytic enzymes of this kind can degrade and inactivate not only endogenous surfactant, but also exogenous lung surfactants used in treating clinical acute lung injury and the acute respiratory distress syndrome (ARDS). All current exogenous surfactant drugs contain substantial contents of glycerophospholipids including 1,2-dipalmitoyl-sn-3-phosphatidylcholine (DPPC), the most prevalent component of endogenous lung surfactant. Phospholipase-induced degradation of glycerophospholipids not only reduces the concentration of active surfactant but also generates byproducts like lysophosphatidylcholine (LPC) and fluid free fatty acids that can further decrease surface activity through biophysical interactions (21, 37, 59). Synthetic exogenous surfactan...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Synthesis and Purification Of Depn-8mentioning

confidence: 99%

Section: Synthesis and Purification Of Depn-8mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Surface activity of a synthetic lung surfactant containing a phospholipase-resistant phosphonolipid analog of dipalmitoyl phosphatidylcholine

Wang¹,

Schwan²,

Lairson³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

show abstract

“…Ester-linked glycerophospholipids of the kind found in native surfactant are the primary lipids used in current synthetic exogenous surfactants. However, synthetic ether-linked lipids are now available that have direct structural analogy to lung surfactant lipids plus designed molecular behavior that enhances adsorption and spreading while maintaining very high dynamic surface tension lowering in surface films (e.g., [71,[205][206][207][208][209][210][211]). Moreover, such lipids have structural features making them resistant to phospholipases such as phospholipase A 2 , which has been implicated in the pathology of ALI/ARDS [65,[212][213][214][215][216][217][218].…”

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