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Activity and Inhibition Resistance of a Phospholipase-Resistant Synthetic Surfactant in Rat Lungs

Departments of ¹ Pediatrics and ² Environmental Medicine, University of Rochester School of Medicine, Rochester, New York; and ³ Department of Chemistry, University of Guelph, Guelph, Ontario, Canada

Correspondence and requests for reprints should be addressed to Robert H. Notter, M.D., Ph.D., Department of Pediatrics, Box 850 (MRBX), University of Rochester School of Medicine, 601 Elmwood Avenue, Rochester, NY 14642. E-mail: Robert_Notter{at}urmc.Rochester.edu

This study investigates the activity and inhibition resistance in excised rat lungs of a novel synthetic surfactant containing the phospholipase-resistant diether phosphonolipid DEPN-8 plus 1.5% bovine surfactant protein (SP)-B/C compared to calf lung surfactant extract (CLSE). DEPN-8 + 1.5% SP-B/C surpassed CLSE in normalizing surfactant-deficient pressure–volume (P–V) deflation mechanics in lavaged excised lungs in the presence of phospholipase A₂ (PLA₂) or C18:1 lyso-phosphatidylcholine (LPC). DEPN-8 + 1.5% SP-B/C had activity equal to CLSE in normalizing P–V mechanics in the absence of inhibitors or in the presence of serum albumin. These physiologic activity findings were directly consistent with surface activity measurements on the pulsating bubble surfactometer. In the absence of inhibitors, DEPN-8 + 1.5% SP-B/C and CLSE rapidly reached minimum surface tensions < 1 mN/m (0.5 and 2.5 mg surfactant phospholipid/ml). DEPN-8 + 1.5% SP-B/C maintained its high surface activity in the presence of PLA₂, while the surface activity of CLSE was significantly inhibited by exposure to this enzyme. DEPN-8 + 1.5% SP-B/C also had greater surface activity than CLSE in the presence of LPC, and the two surfactants had equivalent surface activity in the presence of albumin. DEPN-8 + 1.5% SP-B/C also had slightly greater surface activity than CLSE when exposed to peroxynitrite in pulsating bubble studies. These results support the potential of developing highly active and inhibition-resistant synthetic exogenous surfactants containing DEPN-8 + apoprotein/peptide constituents for use in treating direct pulmonary forms of clinical acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS).

Key Words: synthetic lung surfactants • DEPN-8 • phospholipase resistance • ALI/ARDS • surfactant dysfunction

CLINICAL RELEVANCE This work involves the activity and inhibition resistance of a novel synthetic lung surfactant of potential utility for treating clinical states of lung surfactant deficiency and surfactant dysfunction (ALI/ARDS) in the future.

 

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