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

Abstract

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...

Surfactant for Pediatric Acute Lung Injury

“…In contrast, cell membrane lipids, lyso-phospholipids, or fatty acids act at least in part by mixing into the surface film and compromising its ability to reach low surface tension during dynamic compression [50,55,59,70]. Also, phospholipases, proteases, and reactive oxygen-nitrogen species can act to chemically degrade or alter functionallyessential surfactant lipids or proteins [64,66,71]. It is well-documented that surfactant activity deficits from these various mechanisms can be overcome or at least mitigated in vitro by increasing the concentration of active surfactant even if inhibitor substances are still present [27,46,47].…”

“…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].…”

“…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.…”

Molecular interactions of cord factor with dipalmitoylphosphatidylcholine monolayers: Implications for lung surfactant dysfunction in pulmonary tuberculosis

“…Surface pressure increase was concentration dependent with higher surface pressures reached with lower cord factor concentrations. Attainment of low surface pressure is indicative of lung surfactant dysfunction which otherwise attains higher surface pressure of 70-71 mN/m [5].…”

“…Pulmonary surfactant is a highly surface active phospholipid rich complex lining the human lungs as a spread surfactant monolayer. This surfactant monolayer film reaches higher surface pressures of ∼70-71 mN/m and has a high surface compressibility modulus (SCM) [5]. Presence of such a surface active surfactant film is associated with normal lung physiology.…”