Lysophospholipid generation and phosphatidylglycerol depletion in phospholipase A2-mediated surfactant dysfunction

1 Department of Internal Medicine/Sections of Pulmonary and Critical Care Medicine and 2 Molecular Medicine, Departments of 3 Microbiology and Immunology and 4 Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina Submitted 19 July 2004 ; accepted in final form 13 October 2004 Pulmonary surfactant's complex mixture of phospholipids and proteins reduces the work of breathing by lowering alveolar surface tension during respiration. One mechanism of surfactant damage appears to be the hydrolysis of phospholipid by phospholipases activated in the inflamed lung. Humans have several candidate secretory phospholipase A 2 (sPLA 2 ) enzymes in lung cells and infiltrating leukocytes that could damage extracellular surfactant. We considered two mechanisms of surfactant disruption by five human sPLA 2 s, including generation of lysophospholipids and the depletion of specific phospholipids. All five sPLA 2 s studied ultimately caused surfactant dysfunction. Each enzyme exhibited a different pattern of hydrolysis of surfactant phospholipids. Phosphatidylcholine, the major phospholipid in surfactant and the greatest potential source for generation of lysophospholipids, was susceptible to hydrolysis by group IB, group V, and group X sPLA 2 s, but not group IIA or IID. Group IIA hydrolyzed both phosphatidylethanolamine and phosphatidylglycerol, whereas group IID was active against only phosphatidylglycerol. Thus, with groups IB and X, the generation of lysophospholipids corresponded with surfactant dysfunction. However, hydrolysis of and depletion of phosphatidylglycerol had a greater correlation with surfactant dysfunction for groups IIA and IID. Surfactant dysfunction caused by group V sPLA 2 is less clear and may be the combined result of both mechanisms. lung injury; asthma; surface tension Address for reprint requests and other correspondence: R. D. Hite, Sect. on Pulmonary and Critical Care Medicine, Wake Forest Univ. School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1054 (E-mail: dhite{at}wfubmc.edu